Purine derivatives as adenosine A1 receptor agonists and methods of use thereof

ABSTRACT

The invention relates to Purine Derivatives; compositions comprising an effective amount of a Purine Derivative; and methods for reducing an animal&#39;s rate of metabolism, protecting an animal&#39;s heart against myocardial damage during cardioplegia; or for treating or preventing a cardiovascular disease, a neurological disorder, an ischemic condition, a reperfusion injury, obesity, a wasting disease, or diabetes, comprising administering an effective amount of a Purine Derivative to an animal in need thereof.

This application is a divisional application of U.S. patent applicationSer. No. 11/137,632, filed May 25, 2005, issuing, which claims thebenefit of U.S. provisional application No. 60/574,805, filed May 26,2004, and of U.S. provisional application No. 60/588,263, filed Jul. 15,2004, the disclosure of each of which is incorporated by referenceherein in its entirety.

1. FIELD OF THE INVENTION

The invention relates to Purine Derivatives; compositions comprising aneffective amount of a Purine Derivative; and methods for reducing ananimal's rate of metabolism, protecting an animal's heart againstmyocardial damage during cardioplegia; or for treating or preventing acardiovascular disease, a neurological disorder, an ischemic condition,a reperfusion injury, obesity, a wasting disease, or diabetes,comprising administering an effective amount of a Purine Derivative toan animal in need thereof.

2. BACKGROUND OF THE INVENTION

Adenosine is a naturally occurring purine nucleoside that is ubiquitousin mammalian cell types. Adenosine exerts its biological effects byinteracting with A₁, A₂ (further subclassified as A_(2A) and A_(2B)) andA₃ cell surface receptors, which modulate important physiologicalprocesses.

The A₁ and A_(2A) receptor subtypes are believed to play complementaryroles in adenosine's regulation of a cell's energy supply. Adenosine,which is a metabolic product of ATP, diffuses from the cell and locallyactivates the A₁ receptor to decrease the oxygen demand or activates theA_(2A) receptor to increase the oxygen supply, thereby reinstating thebalance of energy supply and demand within the tissue. The combinedaction of A₁ and A₂ subtypes increases the amount of available oxygen totissue and protects cells against damage caused by a short-termimbalance of oxygen. One of the important functions of endogenousadenosine is to prevent tissue damage during traumas such as hypoxia, anischemic condition, hypotension and seizure activity.

In addition, modulation of A₁ receptors slows conduction velocity in theheart's atrioventricular node, resulting in the normalization ofsupraventricular tachycardias and control of ventricular rate duringatrial fibrillation and flutter. Modulation of A_(2A) receptors alsoregulates coronary vasodilation.

Adenosine is also a neuromodulator, which modulates molecular mechanismsunderlying many aspects of physiological brain function by mediatingcentral inhibitory effects. An increase in neurotransmitter releasefollows traumas such as hypoxia, ischemia and seizures.Neurotransmitters are ultimately responsible for neural degeneration andneural death, which can cause brain damage or death. Adenosine isthought to be an endogenous anticonvulsant agent that inhibits glutamaterelease from excitory neurons and neuronal firing. Adenosine agonists,therefore, are useful as antiepileptic agents.

Adenosine plays an important role as a cardioprotective agent. Levels ofendogenous adenosine increase in response to ischemia and hypoxia andprotect cardiac tissue during and after trauma (preconditioning).Adenosine agonists thus are useful as cardioprotective agents.

The preparation and use of a number of adenosine A₁ receptor agonistshave been described (Moos et al., J. Med. Chem. 28:1383-1384 (1985);Thompson et al., J. Med. Chem. 34:3388-3390 (1991); Vittori et al., J.Med. Chem. 43:250-260 (2000); Roelen et al., J. Med. Chem., 39:1463-1471(1996); van der Wenden et al., J. Med. Chem. 41102-108 (1998); Dalpiazet al., Pharm. Res. 18:531-536 (2001), Beakers et al., J. Med. Chem. 46,1492-1503 (2003); U.S. Pat. No. 5,589,467 to Lau et al.; U.S. Pat. No.5,789,416, to Lum et al.; and C. E. Muller, Current Medicinal Chemistry2000, 7, 1269-1288).

Nucleoside 5′-nitrate esters are reported in Lichtenthaler et al.,Synthesis, 199-201 (1974), and U.S. Pat. No. 3,832,341 to Duchinsky etal.

The citation of any reference in Section 2 of this application is not anadmission that the reference is prior art to this application.

3. SUMMARY OF THE INVENTION

In one embodiment, the invention provides compounds having the Formula(Ia):

and pharmaceutically acceptable salts thereof,wherein

A is —CH₂OSO₂NH₂;

B and C are —OH;

D is:

A and B are trans with respect to each other;

B and C are cis with respect to each other;

C and D are cis or trans with respect to each other;

R¹ is —C₃-C₈ monocyclic cycloalkyl, —C₃-C₈ monocyclic cycloalkenyl,—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkenyl), —C₈-C₁₂ bicyclic cycloalkyl, or —C₈-C₁₂ bicycliccycloalkenyl;

R² is -halo, —CN, —NHR⁸, —OR⁸, —SR⁸, —NHC(O)OR⁸, —NHC(O)R⁴, —NHC(O)NHR⁸,—NHNHC(O)R⁴, —NHNHC(O)OR⁸, —NHNHC(O)NHR⁸, or —NH—N═C(R⁶)R⁷;

R⁴ is —H, —C₁-C₁₅ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₉-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —C≡C—(C₁-C₁₀alkyl) or —C≡C-aryl;

R⁶ is —C₁-C₁₀ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle),—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle),-phenylene-(CH₂)_(n)COOH, or -phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl);

R⁷ is —H, —C₁-C₁₀ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle), or—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle);

R⁸ is —C₁-C₁₅ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —C≡C—(C₁-C₁₀alkyl) or —C≡C-aryl; and

each n is independently an integer ranging from 1 to 5.

In another embodiment, the invention provides compounds having theFormula (Ib):

and pharmaceutically acceptable salts thereof,wherein

A is —CH₂ONO₂;

B and C are —OH;

D is

A and B are trans with respect to each other;

B and C are cis with respect to each other;

C and D are cis or trans with respect to each other;

R¹ is —H, —C₁-C₁₀ alkyl, -aryl, -3- to 7-membered monocyclicheterocycle, -8- to 12-membered bicyclic heterocycle, —C₃-C₈ monocycliccycloalkyl, —C₃-C₈ monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl,—C₈-C₁₂ bicyclic cycloalkenyl —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl;

R² is —CN, —NHR⁴, —NHC(O)R⁴, —NHC(O)OR⁴, —NHC(O)NHR⁴, —NHNHC(O)R⁴,—NHNHC(O)OR⁴, —NHNHC(O)NHR⁴, or —NH—N═C(R⁶)R⁷;

R⁴ is —C₁-C₁₅ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —C≡C—(C₁-C₁₀alkyl) or —C≡C-aryl;

R⁶ is —C₁-C₁₀ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), -phenylene-(CH₂)_(n)COOH, or-phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl);

R⁷ is —H, —C₁-C₁₀ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl) or —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl); and

each n is independently an integer ranging from 1 to 5.

In still another embodiment, the invention provides compounds having theFormula (Ic):

and pharmaceutically acceptable salts thereof,wherein

A is —CH₂NHR⁵;

B and C are —OH;

D is

A and B are trans with respect to each other;

B and C are cis with respect to each other;

C and D are cis or trans with respect to each other;

R¹ is —H, —C₁-C₁₀ alkyl, -aryl, -3- to 7-membered monocyclicheterocycle, -8- to 12-membered bicyclic heterocycle, —C₃-C₈ monocycliccycloalkyl, —C₃-C₈ monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl,—C₈-C₁₂ bicyclic cycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl;

R² is —NHR⁴, —OR⁴, —SR⁴, —NHC(O)R⁴, —NHC(O)OR⁴, —NHC(O)NHR⁴,—NHNHC(O)R⁴, —NHNHC(O)NHR⁴, or —NHNHC(O)OR⁴;

R⁴ is —C₁-C₁₅ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocyle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —C≡C—(C₁-C₁₀alkyl) or —C≡C-aryl;

R⁵ is —C(O)O(C₁-C₁₀ alkyl), —C(O)NH(C₁-C₁₀ alkyl), —C(O)N(C₁-C₁₀alkyl)₂, —C(O)NH-aryl, —CH(NH₂)NH₂ or —CH(NH₂)NH(C₁-C₁₀ alkyl); and

each n is independently an integer ranging from 1 to 5.

In a further embodiment, the invention provides compounds having theFormula (Id):

and pharmaceutically acceptable salts thereof,wherein

A is —R³;

B and C are —OH;

D is

A and B are trans with respect to each other;

B and C are cis with respect to each other;

C and D are cis or trans with respect to each other;

R¹ is —H, —C₁-C₁₀ alkyl, -aryl, -3- to 7-membered monocyclicheterocycle, -8- to 12-membered bicyclic heterocycle, —C₃-C₈ monocycliccycloalkyl, —C₃-C₈ monocyclic cycloalkenyl, —C₃-C₈ monocycliccycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl, —C₈-C₁₂ bicycliccycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl;

R² is —H, -halo, —CN, —NHR⁴, —OR⁴, —SR⁴, —NHC(O)R⁴, —NHC(O)OR⁴,—NHC(O)NHR⁴, NHNHC(O)R⁴, —NHNHC(O)NHR⁴, —NHNHC(O)OR⁴ or —NH—N═C(R⁶)R⁷;

R³ is —CH₂ONO or —CH₂OSO₃H;

R⁴ is —C₁-C₁₅ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —C≡C—(C₁-C₁₀alkyl) or —C≡C-aryl;

R⁶ is —C₁-C₁₀ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle),—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle),-phenylene-(CH₂)_(n)COOH, or -phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl);

R⁷ is —H, —C₁-C₁₀ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle), or—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle); and

each n is independently an integer ranging from 1 to 5.

In a further embodiment, the invention provides compounds having theFormula (Ie):

and pharmaceutically acceptable salts thereof,

wherein

A is —CH₂R³;

B and C are —OH;

D is

A and B are trans with respect to each other;

B and C are cis with respect to each other;

C and D are cis or trans with respect to each other;

R¹ is -3- to 7-membered monocyclic heterocycle, -8- to 12-memberedbicyclic heterocycle, —C₃-C₈ monocyclic cycloalkyl, —C₃-C₈ monocycliccycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl, —C₈-C₁₂ bicycliccycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl;

R² is -halo, —CN, —NHR⁴, —OR⁴, —SR⁴, —NHC(O)R⁴, —NHC(O)OR⁴, —NHC(O)NHR⁴,NHNHC(O)R⁴, —NHNHC(O)OR⁴, —NHNHC(O)NHR⁴, or —NH—N═C(R⁶)R⁷;

R³ is —OSO₂NH(C₁-C₁₀ alkyl), —OSO₂N(C₁-C₁₀ alkyl)₂, or —OSO₂NH-aryl,where each C₁-C₁₀ alkyl is independent;

R⁴ is —C₁-C₁₅ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —C≡C—(C₁-C₁₀alkyl) or —C≡C-aryl;

R⁶ is —C₁-C₁₀ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle),—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle),-phenylene-(CH₂)_(n)COOH, or -phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl);

R⁷ is —H, —C₁-C₁₀ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)-(3- to 7-memberedmonocyclic heterocycle), or —(CH₂)_(n)-(8- to 12-membered bicyclicheterocycle); and

each n is independently an integer ranging from 1 to 5.

In another embodiment, the invention provides compounds having theFormula (If):

and pharmaceutically acceptable salts thereof,wherein

A is —CH₂ONO₂;

B and C are —OH;

D is

A and B are trans with respect to each other;

B and C are cis with respect to each other;

C and D are cis or trans with respect to each other;

R¹ is —C₃-C₈ monocyclic cycloalkyl; and

R² is —H or -halo.

In another embodiment, the invention provides compounds having theFormula (Ig):

and pharmaceutically acceptable salts thereof,wherein

A is —CH₂ONO₂;

B and C are —OH;

D is

A and B are trans with respect to each other;

B and C are cis with respect to each other;

C and D are cis or trans with respect to each other; and

R² is —H or -halo.

In another embodiment, the invention provides compounds having theFormula (Ih):

and pharmaceutically acceptable salts thereof,wherein

A is —CH₂ONO₂;

B and C are —OH;

D is

A and B are trans with respect to each other;

B and C are cis with respect to each other; and

C and D are cis or trans with respect to each other; and

R¹ is cyclopent-1-ol-2-yl, or cyclopent-1-ol-3-yl.

In another embodiment, the invention provides compounds having theFormula (II):

and pharmaceutically acceptable salts thereof,wherein

A is —CH₂OH;

B and C are —H;

D is

A and B are trans with respect to each other;

B and C are cis with respect to each other;

C and D are cis or trans with respect to each other;

each R¹ is independently —H, —C₁-C₁₀ alkyl, —(CH₂)_(m)-(3- to 7-memberedmonocyclic heterocycle), —(CH₂)_(m)-(8- to 12-membered bicyclicheterocycle), —(CH₂)_(m)—(C₈-C₁₂ bicyclic cycloalkyl),—(CH₂)_(m)—(C₈-C₁₂ bicyclic cycloalkenyl), or —(CH₂)_(n)-aryl, or bothR¹ groups together with the carbon atom to which they are attached forma —C₃-C₈ monocyclic cycloalkyl, a —C₃-C₈ monocyclic cycloalkenyl, a—C₈-C₁₂ bicyclic cycloalkyl, or a —C₈-C₁₂ bicyclic cycloalkenyl;

R² is —OR⁴, —SR⁴, —NHNHC(O)R³, —NHNHC(O)NHR³, —NHC(O)OR⁷, or—NH—N═C(R⁵)R⁶;

R³ is —H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to 7-membered monocyclicheterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-aryl,—O—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —O—(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), O—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl;

R⁴ is —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to 7-membered monocyclicheterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkenyl), —(CH₂)_(n)—(C₉-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)-aryl,or —C≡C-aryl;

R⁵ and R⁶ are each independently —H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-aryl,-phenylene-(CH₂)_(n)COOH, or -phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl), orR⁵ and R⁶ together with the carbon atom to which they are attached forma C₃-C₈ monocyclic cycloalkyl or a C₈-C₁₂ bicyclic cycloalkyl;

R⁷ is —H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to 7-membered monocyclicheterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-aryl, —C≡C—(C₁-C₁₀alkyl) or —C≡C-aryl;

m is an integer ranging from 0 to 3; and

each n is independently an integer ranging from 0 to 5.

In still another embodiment, the invention provides compounds having theFormula (III):

and pharmaceutically acceptable salts thereof,wherein

A is —CH₂R³;

B and C are —OH;

D is

A and B are trans with respect to each other;

B and C are cis with respect to each other;

C and D are cis or trans with respect to each other;

each R¹ is independently —H, —C₁-C₁₀ alkyl, —(CH₂)_(m)-(3- to 7-memberedmonocyclic heterocycle), —(CH₂)_(m)-(8- to 12-membered bicyclicheterocycle), —(CH₂)_(m)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(m)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(m)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(m)-aryl, or two R¹ groups, together with the carbon atom towhich they are attached, form a —C₃-C₈ monocyclic cycloalkyl, a —C₃-C₈monocyclic cycloalkenyl, a —C₈-C₁₂ bicyclic cycloalkyl, or a —C₈-C₁₂bicyclic cycloalkenyl;

R² is —H, —CN, -halo, —N(R⁴)₂, —OR⁴, —SR⁴, —NHC(O)R⁴, —NHC(O)OR⁴,—NHC(O)NHR⁴, —NHNHC(O)R⁴, —NHNHC(O)NHR⁴, —NHNHC(O)OR⁴, or —NH—N═C(R⁶)R⁷;

R³ is —ONO₂, —ONO, —OSO₃H, —OSO₂NH₂, —OSO₂NH(C₁-C₁₀ alkyl),—OSO₂N(C₁-C₁₀ alkyl)₂, —OSO₂NH-aryl or —N(R⁵)₂;

each R⁴ is independently —H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to 7-memberedmonocyclic heterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclicheterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-aryl,—C(O)O(C₁-C₁₀ alkyl), —C(O)NH(C₁-C₁₀ alkyl), —C(O)N(C₁-C₁₀ alkyl)₂,—C(O)NH-aryl, —C(O)N(C₁-C₁₀ alkyl)₂, —CH(NH₂)NH₂ or —CH(NH₂)NH(C₁-C₁₀alkyl);

each R⁵ is independently —H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to 7-memberedmonocyclic heterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclicheterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl) or—(CH₂)_(n)-aryl;

R⁶ and R⁷ are each independently —H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-aryl,-phenylene-(CH₂)_(n)COOH, or -phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl), orR⁶ and R⁷, together with the carbon atom to which they are attached,form a —C₃-C₈ monocyclic cycloalkyl, —C₃-C₈ monocyclic cycloalkenyl, ora C₈-C₁₂ bicyclic cycloalkenyl;

m is an integer ranging from 0 to 3; and

each n is independently an integer ranging from 0 to 5.

In a further embodiment, the invention provides compounds having theFormula (IV):

and pharmaceutically acceptable salts thereof,wherein

A is —CH₂OH;

B and C are —OH;

D is

A and B are trans with respect to each other;

B and C are cis with respect to each other;

C and D are cis or trans with respect to each other;

R¹ is —C₃-C₈ monocyclic cycloalkyl or —C₃-C₈ monocyclic cycloalkenyl;

R² is —H, -halo, —CN, —OR³, —SR³, —N(R³)₂, —NHNHC(O)R³, —NHNHC(O)NHR³,—NHNHC(O)OR³, or —NH—N═C(R⁴)R⁵;

each R³ is independently —H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to 7-memberedmonocyclic heterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclicheterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-aryl,—C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl;

R⁴ and R⁵ are each independently —H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-aryl,-phenylene-(CH₂)_(n)COOH, or -phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl), orR⁴ and R⁵ together with the carbon atom to which they are attached forma C₃-C₈ monocyclic cycloalkyl, a C₃-C₈ monocyclic cycloalkenyl, a—C₈-C₁₂ bicyclic cycloalkyl, or a —C₈-C₁₂ bicyclic cycloalkenyl; and

each n is independently an integer ranging from 0 to 5.

In another embodiment, the invention provides compounds having theFormula (V):

and pharmaceutically acceptable salts thereof,wherein

A is —CH₂OH;

B and C are —OH;

D is

A and B are trans with respect to each other;

B and C are cis with respect to each other;

C and D are cis or trans with respect to each other;

R¹ is —C₁-C₁₀ alkyl, —(CH₂)_(m)-(3- to 7-membered monocyclicheterocycle), —(CH₂)_(m)-(8- to 12-membered bicyclic heterocycle),—(CH₂)_(m)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(m)—(C₃-C₈ monocyclic cycloalkenyl) or —(CH₂)_(m)-aryl, or R¹ andR^(1a) together with the carbon atom to which they are attached form a—C₃-C₈ monocyclic cycloalkyl, a —C₃-C₈ monocyclic cycloalkenyl, a—C₈-C₁₂ bicyclic cycloalkyl, or a —C₈-C₁₂ bicyclic cycloalkenyl;

R^(1a) is —C₃-C₈ monocyclic cycloalkyl or —C₃-C₈ monocycliccycloalkenyl;

R² is —OR⁴, —SR⁴, —NHNHC(O)R³, —NHNHC(O)NHR³, —NHNHC(O)OR³, or—NH—N═C(R⁵)R⁶;

R³ is —H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to 7-membered monocyclicheterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclic-heterocycle),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-aryl, —C≡C—(C₁-C₁₀alkyl) or —C≡C-aryl;

R⁴ is —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to 7-membered monocyclicheterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)-aryl,—C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl;

R⁵ and R⁶ are each independently —H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-aryl,-phenylene-(CH₂)_(n)COOH, or -phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl), orR⁵ and R⁶ together with the carbon atom to which they are attached forma C₃-C₈ monocyclic cycloalkyl, a C₃-C₈ monocyclic cycloalkenyl, a—C₈-C₁₂ bicyclic cycloalkyl, or a —C₈-C₁₂ bicyclic cycloalkenyl;

m is an integer ranging from 0 to 3; and

each n is independently an integer ranging from 0 to 5.

A compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(II), (III), (IV) or (V) or a pharmaceutically acceptable salt thereof,(a “Purine Derivative”) is useful for: (i) treating or preventing acardiovascular disease, a neurological disorder, an ischemic condition,a reperfusion injury, obesity, a wasting disease, or diabetes (eachbeing a “Condition”); (ii) reducing an animal's rate of metabolism; or(iii) protecting an animal's heart against myocardial damage duringcardioplegia

The invention also provides compositions comprising an effective amountof a Purine Derivative and a physiologically acceptable carrier orvehicle. The compositions are useful for: (i) treating or preventing aCondition; (ii) reducing an animal's rate of metabolism; or (iii)protecting an animal's heart against myocardial damage duringcardioplegia.

The invention further provides methods for: (i) treating or preventing aCondition; (ii) reducing an animal's rate of metabolism; or (iii)protecting an animal's heart against myocardial damage duringcardioplegia, comprising administering an effective amount of a PurineDerivative to an animal in need thereof.

The details of the invention are set forth in the accompanyingdescription below. Other features, objects, and advantages of theinvention will be apparent from the description and from the claims. Allpatents, patent applications and publications cited in thisspecification are incorporated herein by reference for all purposes.

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of Compound 17 on lipopolysaccharide inducedplasma TNF and MIP production in male BALB/c mice. The unshaded barsrepresent LPS, administered i.p. at a dose of 1 mg/kg and the shadedbars represent Compound 17, administered orally at a dose of 0.03 mg/kg,followed 30 minutes later by LPS, administered i.p. at a dose of 1mg/kg. TNF and MIP levels were measured 90 minutes after LPSadministration.

FIG. 2 shows the effect of Compound 17 in survival studies in maleBALB/c mice, expressed as the percentage of surviving animals at 10-hourtime intervals. Line -□- represents LPS, administered i.p. at a dose of55 mg/kg, and line -♦- represents Compound 17, administered orally at adose of 0.03 mg/kg, followed 30 minutes later by LPS, administered i.p.at a dose of 55 mg/kg.

FIG. 3 shows the effects of Compound 17 on the duration ofischemia-induced arrhythmias in isolated perfused rat hearts. The bargraph from left to right, represents: a non-treated control group,Compound 17 administered at 10 pM, Compound 17 administered at 30 pM,and Compound 17 administered at 100 pM, respectively.

FIG. 4 shows the effect of Compound 17 on function recovery in isolatedperfused rat hearts after 30 minute no-flow ischemia followed by 40minute reperfusion. Line -▴- represents a non-treated control group(n=13) and line -▪- represents administration (n=9) of Compound 17 at aconcentration of 1 nM, administered 10 minutes prior to induction ofischemia

FIG. 5 shows the effect of Compound 17 and/or buprenorphine in an acutepain model in mice using a tail flick assay. The X-axis representsMaximum Possible Effect (MPE) and the Y-axis represents time afteradministration of Compound 17 and/or buprenorphine. Line -●- representsco-administration of buprenorphine (1.0 mg/kg) and Compound 17 (3.0mg/kg), line -▪- represents buprenorphine (1.0 mg/kg), line -▴-represents Compound 17 (3.0 mg/kg), line —X— representsco-administration of buprenorphine (0.3 mg/kg) and Compound 17 (3.0mg/kg), and line -

- represents buprenorphine (0.3 mg/kg).

FIG. 6 shows the effect of Compound 17 in a mouse formalin pain modelpain. The bar graph from left to right shows the first phase of the test(no response) and the second phase of the test (shaded bar).

FIG. 7 shows the effect of Compound 17 on allodynia in a mouse model ofdiabetic neuropathy. The X-axis represents the animal's pain thresholdand the Y-axis represents time after administration of Compound 17. Line-●- represents treatment with Compound 17 (1.0 mg/kg).

FIG. 8 shows the effect of Compound 17 on mechanically induced painthreshold in a carrageenan rat model. The X-axis represents the animal'spain threshold and the Y-axis represents time after administration ofCompound 17. Line -∘- represents vehicle and line -▪-represents Compound17 (5.0 mg/kg).

FIG. 9 shows the effect of Compound 17 and/or buprenorphine on painthreshold in a mouse model of sciatic nerve ligation. The k-axisrepresents the animal's pain threshold and the Y-axis represents timeafter administration of Compound 17 and or buprenorphine. The top leftgraph shows the effect of vehicle, the top right graph shows the effectof Compound 17 (0.1 mg/kg), the bottom left graph shows the effect ofbuprenorphine (0.3 mg/kg) and the bottom right graph shows the effect ofco-administration of Compound 17 (0.1 mg/kg) and buprenorphine (0.3mg/kg). Line -♦- represents the response of the control leg and line -▪-represents the response of the treated leg.

5. DETAILED DESCRIPTION OF THE INVENTION 5.1 Definitions

The term “C₁-C₁₅ alkyl” as used herein refers to a straight or branchedchain, saturated hydrocarbon having from 1 to 15 carbon atoms.Representative C₁-C₁₅ alkyl groups include, but are not limited tomethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-buty, pentyl,isopentyl, neopentyl, hexyl, isohexyl, neohexyl, heptyl, isoheptyl,neoheptyl, octyl, isooctyl, neooctyl, nonyl, isononyl, neononyl, decyl,isodecyl, neodecyl, undecyl, dodecyl, tridecyl, tetradecyl andpentadecyl. In one embodiment, the C₁-C₁₅ alkyl group is substitutedwith one or more of the following groups: -halo, —O—(C₁-C₆ alkyl), —OH,—CN, —COOR′, —OC(O)R′, —N(R′)₂, —NHC(O)R′ or —C(O)NHR′ groups whereineach R′ is independently —H or unsubstituted —C₁-C₆ alkyl. Unlessindicated, the C₁-C₁₅ alkyl is unsubstituted.

The term “C₁-C₁₀ alkyl” as used herein refers to a straight or branchedchain, saturated hydrocarbon having from 1 to 10 carbon atoms.Representative C₁-C₁₀ alkyl groups include, but are not limited tomethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, isohexyl, neohexyl, heptyl, isoheptyl,neoheptyl, octyl, isooctyl, neooctyl, nonyl, isononyl, neononyl, decyl,isodecyl and neodecyl. In one embodiment, the C₁-C₁₀ alkyl group issubstituted with one or more of the following groups: -halo, —O—(C₁-C₆alkyl), —OH, —CN, —COOR′, —OC(O)R′, —N(R′)₂, —NHC(O)R′ or —C(O)NHR′groups wherein each R′ is independently —H or unsubstituted —C₁-C₆alkyl. Unless indicated, the C₁-C₁₀ alkyl is unsubstituted.

The term “C₁-C₆ alkyl” as used herein refers to a straight or branchedchain, saturated hydrocarbon having from 1 to 6 carbon atoms.Representative C₁-C₆ alkyl groups include, but are not limited tomethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-buty, pentyl,isopentyl, neopentyl, hexyl, isohexyl, and neohexyl. Unless indicated,the C₁-C₆ alkyl is unsubstituted.

The term “aryl” as used herein refers to a phenyl group or a naphthylgroup. In one embodiment, the aryl group is substituted with one or moreof the following groups: -halo, —O—(C₁-C₆ alkyl), —OH, —CN, —COOR′,—OC(O)R′, —N(R′)₂, —NHC(O)R′ or —C(O)NHR′ groups wherein each R′ isindependently —H or unsubstituted —C₁-C₆ alkyl. Unless indicated, thearyl is unsubstituted.

The term “C₃-C₈ monocyclic cycloalkyl” as used herein is a 3-, 4-, 5-,6-, 7- or 8-membered saturated non-aromatic monocyclic cycloalkyl ring.Representative C₃-C₈ monocyclic cycloalkyl groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl. In one embodiment, the C₃-C₈ monocycliccycloalkyl group is substituted with one or more of the followinggroups: -halo, —O—(C₁-C₆ alkyl), —OH, —CN, —COOR′, —OC(O)R′, —N(R′)₂,—NHC(O)R′ or —C(O)NHR′ groups wherein each R′ is independently —H orunsubstituted —C₁-C₆ alkyl. Unless indicated, the C₃-C₈ monocycliccycloalkyl is unsubstituted.

The term “C₃-C₈ monocyclic cycloalkenyl” as used herein is a 3-, 4-, 5-,6-, 7- or 8-membered non-aromatic monocyclic carbocyclic ring having atleast one endocyclic double bond, but which is not aromatic. It is to beunderstood that when any two groups, together with the carbon atom towhich they are attached form a C₃-C₈ monocyclic cycloalkenyl group, thecarbon atom to which the two groups are attached remains tetravalent.Representative C₃-C₈ monocyclic cycloalkenyl groups include, but are notlimited to, cyclopropenyl, cyclobutenyl, 1,3-cyclobutadienyl,cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,3-cyclohexadienyl,cycloheptenyl, 1,3-cycloheptadienyl, 1,4-cycloheptadienyl,-1,3,5-cycloheptatrienyl, cyclooctenyl, 1,3-cyclooctadienyl,1,4-cyclooctadienyl, -1,3,5-cyclooctatrienyl. In one embodiment, theC₃-C₈ monocyclic cycloalkenyl group is substituted with one or more ofthe following groups: -halo, —O—(C₁-C₆ alkyl), —OH, —CN, —COOR′,—OC(O)R′, —N(R′)₂, —NHC(O)R′ or —C(O)NHR′ groups wherein each R′ isindependently —H or unsubstituted —C₁-C₆ alkyl. Unless indicated, theC₃-C₈ monocyclic cycloalkenyl is unsubstituted.

The term “C₈-C₁₂ bicyclic cycloalkyl” as used herein is a 8-, 9-, 10-,11- or 12-membered saturated, non-aromatic bicyclic cycloalkyl ringsystem. Representative C₈-C₁₂ bicyclic cycloalkyl groups include, butare not limited to, decahydronaphthalene, octahydroindene,decahydrobenzocycloheptene, and dodecahydroheptalene. In one embodiment,the C₈-C₁₂ bicyclic cycloalkyl group is substituted with one or more ofthe following groups: -halo, —O—(C₁-C₆ alkyl), —OH, —CN, —COOR′,—OC(O)R′, —N(R′)₂, —NHC(O)R′ or —C(O)NHR′ groups wherein each R′ isindependently —H or unsubstituted —C₁-C₆ alkyl.

Unless indicated, the C₈-C₁₂ bicyclic cycloalkyl is unsubstituted.

The term “C₈-C₁₂ bicyclic cycloalkenyl” as used herein is a 8-, 9-, 10-,11- or 12-membered non-aromatic bicyclic cycloalkyl ring system, havingat least one endocyclic double bond. It is to be understood that whenany two groups, together with the carbon atom to which they are attachedform a C₈-C₁₂ bicyclic cycloalkenyl group, the carbon atom to which thetwo groups are attached remains tetravalent. Representative C₈-C₁₂bicyclic cycloalkenyl groups include, but are not limited to,octahydronaphthalene, hexahydronaphthalene, hexahydroindene,tetrahydroindene, octahydrobenzocycloheptene,hexahydrobenzocycloheptene, tetrahydrobenzocyclopheptene,decahydroheptalene, octahydroheptalene, hexahydroheptalene, andtetrahydroheptalene. In one embodiment, the C₈-C₁₂ bicyclic cycloalkylgroup is substituted with one or more of the following groups: -halo,—O—(C₁-C₆ alkyl), —OH, —CN, —COOR′, —OC(O)R′, —N(R′)₂, —NHC(O)R′ or—C(O)NHR′ groups wherein each R′ is independently —H or unsubstituted—C₁-C₆ alkyl. Unless indicated, the C₈-C₁₂ bicyclic cycloalkenyl isunsubstituted.

The term “effective amount” as used herein refers to an amount of aPurine Derivative that is effective for: (i) treating or preventing aCondition; (ii) reducing an animal's rate of metabolism; or (iii)protecting an animal's heart against myocardial damage duringcardioplegia.

The term “halo” as used herein refers to —F, —Cl, —Br or —I.

The term “3- to 7-membered monocyclic heterocycle” refers to: (i) a 3-or 4-membered non-aromatic monocyclic cycloalkyl in which 1 of the ringcarbon atoms has been replaced with an N, O or S atom; or (ii) a 5-, 6-,or 7-membered aromatic or non-aromatic monocyclic cycloalkyl in which1-4 of the ring carbon atoms have been independently replaced with a N,O or S atom. The non-aromatic 3- to 7-membered monocyclic heterocyclescan be attached via a ring nitrogen, sulfur, or carbon atom. Thearomatic 3- to 7-membered monocyclic heterocycles are attached via aring carbon atom. Representative examples of a 3- to 7-memberedmonocyclic heterocycle-group include, but are not limited to furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isothiazolyl,isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl,oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,piperazinyl, -piperidinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimuidazole,pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,quinuclidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiomorpholinyl,thiophenyl, triazinyl, triazolyl, In one embodiment, the 3- to7-membered monocyclic heterocycle group is substituted with one or moreof the following groups: -halo, —O—(C₁-C₆ alkyl), —OH, —CN, —COOR′,—OC(O)R′, —N(R′)₂, —NHC(O)R′ or —C(O)NHR′ groups wherein each R′ isindependently —H or unsubstituted —C₁-C₆ alkyl. Unless indicated, the 3-to 7-membered monocyclic heterocycle is unsubstituted.

The term “8- to 12-membered bicyclic heterocycle” refers to a bicyclic8- to 12-membered aromatic or non-aromatic bicyclic cycloalkyl in whichone or both of the of the rings of the bicyclic ring system have 14 ofits ring carbon atoms independently replaced with a N, O or S atom.Included in this class are 3- to 7-membered monocyclic heterocycles thatare fused to a benzene ring. A non-aromatic ring of an 8- to 12-memberedmonocyclic heterocycle is attached via a ring nitrogen, sulfur, orcarbon atom. An aromatic 8- to 12-membered monocyclic heterocycles areattached via a ring carbon atom. Examples of 8- to 12-membered bicyclicheterocycles include, but are not limited to, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrzolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolinyl, cinnolinyl, decahydroquinolinyl,1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,isobenzofuranyl, isoindazolyl, isoindolyl, isoindolinyl, isoquinolinyl,naphthyridinyl, octahydroisoquinolinyl, phthalazinyl, pteridinyl,purinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,and xanthenyl. In one embodiment, each ring of a the -8- to 12-memberedbicyclic heterocycle group can substituted with one or more of thefollowing groups: -halo, —O—(C₁-C₆ alkyl), —OH, —CN, —COOR′, —OC(O)R′,—N(R′)₂, —NHC(O)R′ or —C(O)NHR′ groups wherein each R′ is independently—H or unsubstituted —C₁-C₆ alkyl. Unless indicated, the 8- to12-membered bicyclic heterocycle is unsubstituted.

Representative examples of a “phenylene group” are depicted below:

The phrase “pharmaceutically acceptable salt,” as used herein, is a saltof an acid and a basic nitrogen atom of a Purine Derivative.Illustrative salts include, but are not limited, to sulfate, citrate,acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate,phosphate, acid phosphate, isonicotinate, lactate, salicylate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate(i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Thepharmaceutically acceptable salt can also be a camphorsulfonate salt.The term “pharmaceutically acceptable salt” also refers to a salt of aPurine Derivative having an acidic functional group, such as acarboxylic acid functional group, and a base. Suitable bases include,but are not limited to, hydroxides of alkali metals such as sodium,potassium, and lithium; hydroxides of alkaline earth metal such ascalcium and magnesium; hydroxides of other metals, such as aluminum andzinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-OH-lower alkylamines), such asmono-; bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine,or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxyl-loweralkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine, and the like. The term “pharmaceutically acceptablesalt” also includes a hydrate of a Purine Derivative.

An “animal” is a mammal, e.g., a human, mouse, rat, guinea pig, dog,cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus. In one embodiment, an animal is a human.

The term “isolated and purified” as used herein means separate fromother components of a reaction mixture or natural source. In certainembodiments, the isolate contains at least 30%, at least 35%, at least40%, at least 45%, at least 50%, at least 55%, at least 60%, at least65%, at least 70%, at least 75%, at least 80%, at least 85%, at least90%, at least 95% or at least 98% of a Purine Derivative by weight ofthe isolate. In one embodiment, the isolate contains at least 95% of aPurine Derivative by weight of the isolate.

The term “substantially free of its corresponding opposite enantiomer”as used herein, means that a Purine Derivative contains no more thanabout 10% by weight of its corresponding opposite enantiomer. In oneembodiment the Purine Derivative that is substantially free of itscorresponding opposite enantiomer contains no more than about 5% byweight of its corresponding opposite enantiomer. In a further embodimenta Purine Derivative that is substantially free of its correspondingopposite enantiomer contains no more than about 1% by weight of itscorresponding opposite enantiomer. In another embodiment a PurineDerivative that is substantially free of its corresponding oppositeenantiomer contains no more than about 0.5% by weight of itscorresponding opposite enantiomer. In still another embodiment a PurineDerivative that is substantially free of its corresponding oppositeenantiomer contains no more than about 0.1% by weight of itscorresponding opposite enantiomer.

The term “substantially free of its corresponding other anomer” as usedherein, means that a Purine Derivative contains no more than about 10%by weight of its corresponding other anomer. In one embodiment thePurine Derivative that is substantially free of its corresponding otheranomer contains no more than about 5% by weight of its correspondingother anomer. In a further embodiment a Purine Derivative that issubstantially free of its corresponding other anomer contains no morethan about 1% by weight of its corresponding other anomer. In anotherembodiment a Purine Derivative that is substantially free of itscorresponding other anomer contains no more than about 0.5% by weight ofits corresponding other anomer. In still another embodiment a PurineDerivative that is substantially free of its corresponding other anomercontains no more than about 0.1% by weight of its corresponding otheranomer.

Some chemical structures herein are depicted using bold and dashed linesto represent chemical bonds. These bold and dashed lines depict absolutestereochemistry. A bold line indicates that a substituent is above theplane of the carbon atom to which it is attached and a dashed lineindicates that a substituent is below the plane of the carbon atom towhich it is attached. For example, in the illustration below:

group A is above the plane of the carbon atom to which it is attachedand group B is below the plane of the carbon atom to which it isattached.

The following abbreviations are used herein and have the indicateddefinitions: Ac₂O is acetic anhydride; ATP is adenosine triphosphate;CCPA is 2-chloro-N⁶-cyclopentyladenosine; CPA isN⁶-cyclopentyladenosine; CSA is camphorsulfonic acid; CHO is chinesehamster ovary; DMF is N,N-dimethylformamide; EGTA is ethylene glycolbis(3-aminoethyl ether)-N,N,N′,N′-tetraacetic acid; EtNH₂ is ethylamine;EtOAc is ethyl acetate; EtOH is ethanol; LiHMDS is lithiumhexamethyldisilazide; MeOH is methanol; MS is mass spectrometry; NECA isadenosine-5′-(N-ethyl)carboxamido; NMR is nuclear magnetic resonance;R-PIA is N⁶-(2-phenyl-isopropyl) adenosine, R-isomer; TFA istrifluoroacetic acid; THF is tetrahydrofuran; TMSOTf is trimethylsilyltrifluoromethanesulfonate.

5.2 The Purine Derivatives 5.2.1 The Purine Derivatives of Formula (Ia)

As stated above, the present invention encompasses Purine Derivativeshaving the Formula (Ia):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ia), and A and B are trans with respect to each other; B and Care cis with respect to each other; and C and D are cis or trans withrespect to each other.

In one embodiment, R¹ is —C₃-C₈ monocyclic cycloalkyl.

In a specific embodiment, R¹ is cyclopentyl.

In another embodiment, R¹ is —C₃-C₈ monocyclic cycloalkenyl.

In another embodiment, R¹ is —C₈-C₁₂ bicyclic cycloalkyl or —C₈-C₁₂bicyclic cycloalkenyl.

In still another embodiment, R¹ is —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkyl) or —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl).

In one embodiment, R² is -halo.

In a specific embodiment, R² is —Cl.

In another embodiment, R² is —CN.

In another embodiment, R² is —NHR⁸, —OR⁸ or —SR⁸.

In a further embodiment, R² is —NHC(O)R⁴, —NHC(O)OR⁸ or —NHC(O)NHR⁸.

In another embodiment, R² is —NHNHC(O)R⁴, —NHNHC(O)OR⁸ or —NHNHC(O)NHR⁸.In yet another embodiment, R² is —NH—N═C(R⁶)R⁷.

In one embodiment, C and D are cis with respect to each other.

In another embodiment, C and D are trans with respect to each other.

The present invention also provides compositions comprising an effectiveamount of a Purine Derivative of Formula (Ia) and a physiologicallyacceptable carrier or vehicle.

The invention further provides Purine Derivatives of Formula (Ia) thatare in isolated and purified form.

The invention still further provides methods for treating or preventinga Condition, comprising administering an effective amount of a PurineDerivative of Formula (Ia) to an animal in need thereof.

The invention further provides methods for reducing an animal's rate ofmetabolism, comprising administering an effective amount of a PurineDerivative of Formula (Ia) to an animal in need thereof.

The invention further provides methods for protecting an animal's heartagainst myocardial damage during cardioplegia, comprising administeringan effective amount of a Purine Derivative of Formula (Ia) to an animalin need thereof.

The Purine Derivatives of Formula (Ia) can exist in the form of a singleenantiomer, for example, that depicted by either the Formula (Ia′) orFormula (Ia″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ia).

A Purine Derivative of Formula (Ia′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Ia″) when group A of thePurine Derivative of Formula (Ia′) is the same as group A of the PurineDerivative of Formula (Ia″) and when group D of the Purine Derivative ofFormula (Ia′) is the same as group D of the Purine Derivative of Formula(Ia″).

A Purine Derivative of Formula (Ia″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Ia″) when group A of thePurine Derivative of Formula (Ia″) is the same as group A of the PurineDerivative of Formula (Ia′) and when group D of the Purine Derivative ofFormula (Ia″) is the same as group D of the Purine Derivative of Formula(Ia′).

In one embodiment, the Purine Derivatives of Formula (Ia) have theformula (Ia′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ia), and wherein the PurineDerivatives of Formula (Ia′) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (Ia) have theformula (Ia″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ia), and wherein the PurineDerivatives of Formula (Ia″) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (Ia) exist as amixture of a Purine Derivative of Formula (Ia′) and a Purine Derivativeof Formula (Ia″) wherein the amount of the Purine Derivative of Formula(Ia′) exceeds the amount of the Purine Derivative of Formula (Ia″).

In a further embodiment, the Purine Derivatives of Formula (Ia) exist asa mixture of a Purine Derivative of Formula (Ia′) and a PurineDerivative of Formula (Ia″) wherein the amount of the Purine Derivativeof Formula (Ia″) exceeds the amount of the Purine Derivative of Formula(Ia′).

In another embodiment, the Purine Derivatives of Formula (Ia) exist as aracemic mixture of a Purine Derivative of Formula (Ia′) and a PurineDerivative of Formula (Ia″).

In another embodiment, the Purine Derivatives of Formula (Ia) can existin the form of a single enantiomer, for example, that depicted by eitherformula (Iaa′) or (Iaa″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ia).

A Purine Derivative of Formula (Iaa′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Iaa″) when group A of thePurine Derivative of Formula (Iaa′) is the same as group A of the PurineDerivative of Formula (Iaa″) and when group D of the Purine Derivativeof Formula (Iaa′) is the same as group D of the Purine Derivative ofFormula (Iaa″).

A Purine Derivative of Formula (Iaa″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Iaa′) when group A of thePurine Derivative of Formula (Iaa″) is the same as group A of the PurineDerivative of Formula (Iaa′) and when group D of the Purine Derivativeof Formula (Iaa″) is the same as group D of the Purine Derivative ofFormula (Iaa′).

In one embodiment, the Purine Derivatives of Formula (Ia) have theformula (Iaa′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ia), and wherein the PurineDerivatives of Formula (Iaa′) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (Ia) have theformula (Iaa″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ia), and wherein the PurineDerivatives of Formula (Iaa″) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (Ia) exist as amixture of a Purine Derivative of Formula (Iaa′) and a Purine Derivativeof Formula (Iaa″) wherein the amount of the Purine Derivative of Formula(Iaa′) exceeds the amount of the Purine Derivative of Formula (Iaa″).

In a further embodiment, the Purine Derivatives of Formula (Ia) exist asa mixture of a Purine Derivative of Formula (Iaa′) and a PurineDerivative of Formula (Iaa″) wherein the amount of the Purine Derivativeof Formula (Iaa″) exceeds the amount of the Purine Derivative of Formula(Iaa′).

In another embodiment, the Purine Derivatives of Formula (Ia) exist as aracemic mixture of a Purine Derivative of Formula (Iaa′) and a PurineDerivative of Formula (Iaa″).

A Purine Derivative of Formula (Iaa′) is the corresponding other anomerof a Purine Derivative of Formula (Ia′) when group A of the PurineDerivative of Formula (Iaa′) is the same as group A of the PurineDerivative of Formula (Ia′) and when group D of the Purine Derivative ofFormula (Iaa′) is the same as group D of the Purine Derivative ofFormula (Ia′).

A Purine Derivative of Formula (Ia′) is the corresponding other anomerof a Purine Derivative of Formula (Iaa′) when group A of the PurineDerivative of Formula (Ia′) is the same as group A of the PurineDerivative of Formula (Iaa′) and when group D of the Purine Derivativeof Formula (Ia′) is the same as group D of the Purine Derivative ofFormula (Iaa′).

A Purine Derivative of Formula (Iaa′) is the corresponding other anomerof a Purine Derivative of Formula (Ia″) when group A of the PurineDerivative of Formula (Iaa″) is the same as group A of the PurineDerivative of Formula (Ia″) and when group D of the Purine Derivative ofFormula (Iaa″) is the same as group D of the Purine Derivative ofFormula (Ia″).

A Purine Derivative of Formula (Ia″) is the corresponding other anomerof a Purine Derivative of Formula (Iaa″) when group A of the PurineDerivative of Formula (Ia″) is the same as group A of the PurineDerivative of Formula (Iaa″) and when group D of the Purine Derivativeof Formula (Ia″) is the same as group D of the Purine Derivative ofFormula (Iaa″).

In one embodiment, the Purine Derivatives of Formula (Ia) have theformula (Iaa′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ia), and wherein the PurineDerivatives of Formula (Iaa′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (Ia) have theformula (Iaa″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ia), and wherein the PurineDerivatives of Formula (Iaa″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (Ia) have theformula (Ia′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ia), and wherein the PurineDerivatives of Formula (Ia′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (Ia) have theformula (Ia″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ia), and wherein the PurineDerivatives of Formula (Ia″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (Ia) exist as amixture of a Purine Derivative of Formula (Ia′) and a Purine Derivativeof Formula (Iaa′) wherein the amount of the Purine Derivative of Formula(Ia′) exceeds the amount of the Purine Derivative of Formula (Iaa′).

In another embodiment, the Purine Derivatives of Formula (Ia) exist as amixture of a Purine Derivative of Formula (Ia′) and a Purine Derivativeof Formula (Iaa′) wherein the amount of the Purine Derivative of Formula(Iaa′) exceeds the amount of the Purine Derivative of Formula (Ia′).

In a further embodiment, the Purine Derivatives of Formula (Ia) exist asa equal mixture of a Purine Derivative of Formula (Ia′) and a PurineDerivative of Formula (Iaa′).

In one embodiment, the Purine Derivatives of Formula (Ia) exist as amixture of a Purine Derivative of Formula (Ia″) and a Purine Derivativeof Formula (Iaa″) wherein the amount of the Purine Derivative of Formula(Ia″) exceeds the amount of the Purine Derivative of Formula (Iaa″).

In another embodiment, the Purine Derivatives of Formula (Ia) exist as amixture of a Purine Derivative of Formula (Ia″) and a Purine Derivativeof Formula (Iaa″) wherein the amount of the Purine Derivative of Formula(Iaa″) exceeds the amount of the Purine Derivative of Formula (Ia″).

In a further embodiment, the Purine Derivatives of Formula (Ia) exist asa equal mixture of a Purine Derivative of Formula (Ia″) and a PurineDerivative of Formula (Iaa″).

5.2.2 The Purine Derivatives of Formula (Ib)

As stated above, the present invention encompasses Purine Derivativeshaving the Formula (Ib):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ib), and A and B are trans with respect to each other; B and Care cis with respect to each other; and C and D are cis or trans withrespect to each other.

In one embodiment, R¹ is —H.

In another embodiment, R¹ is —C₃-C₈ monocyclic cycloalkyl.

In a specific embodiment, R¹ is cyclopentyl.

In another embodiment, R¹ is —C₃-C₈ monocyclic cycloalkenyl.

In another embodiment, R¹ is —C₈-C₁₂ bicyclic cycloalkyl or —C₈-C₁₂bicyclic cycloalkenyl.

In still another embodiment, R¹ is —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkyl) or —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl).

In another embodiment, R² is —CN.

In another embodiment, R² is —NHR⁴.

In a further embodiment, R² is —NHC(O)R⁴, —NHC(O)OR⁴ or —NHC(O)NHR⁴.

In another embodiment, R² is —NHNHC(O)R⁴, —NHNHC(O)OR⁴ or —NHNHC(O)NHR⁴.

In yet another embodiment, R² is —NH—N═C(R⁶)R⁷.

In one embodiment, C and D are cis with respect to each other.

In another embodiment, C and D are trans with respect to each other.

The present invention also provides compositions comprising an effectiveamount of a Purine Derivative of Formula (Ib) and a physiologicallyacceptable carrier or vehicle.

The invention further provides Purine Derivatives of Formula (Ib) thatare in isolated and purified form.

The invention still further provides methods for treating or preventinga Condition, comprising administering an effective amount of a PurineDerivative of Formula (Ib) to an animal in need thereof.

The invention further provides methods for reducing an animal's rate ofmetabolism, comprising administering an effective amount of a PurineDerivative of Formula (Ib) to an animal in need thereof.

The invention further provides methods protecting an animal's heartagainst myocardial damage during cardioplegia, comprising administeringan effective amount of a Purine Derivative of Formula (Ib) to an animalin need thereof.

The Purine Derivatives of Formula (Ib) can exist in the form of a singleenantiomer, for example, that depicted by either the Formula (Ib′) orFormula (Ib″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ib).

A Purine Derivative of Formula (Ib′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Ib″) when group A of thePurine Derivative of Formula (Ib′) is the same as group A of the PurineDerivative of Formula (Ib″) and when group D of the Purine Derivative ofFormula (Ib′) is the same as group D of the Purine Derivative of Formula(Ib″).

A Purine Derivative of Formula (Ib″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Ib′) when group A of thePurine Derivatives of Formula (Ib″) is the same as group A of the PurineDerivative of Formula (Ib′) and when group D of the Purine Derivative ofFormula (Ib″) is the same as group D of the Purine Derivative of Formula(Ib′).

In one embodiment, the Purine Derivatives of Formula (Ib) have theformula (Ib′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ib), and wherein the PurineDerivatives of Formula (Ib′) are substantially free of theircorresponding enantiomer, represented by Formula (Ib″).

In another embodiment, the Purine Derivatives of Formula (Ib) have theformula (Ib″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ib), and wherein the PurineDerivatives of Formula (Ib″) are substantially free of theircorresponding enantiomer, represented by Formula (Ib′).

In one embodiment, the Purine Derivatives of Formula (Ib) exist as amixture of a Purine Derivative of Formula (Ib′) and a Purine Derivativeof Formula (Ib″) wherein the amount of the Purine Derivative of Formula(Ib′) exceeds the amount of the Purine Derivative of Formula (Ib″).

In another embodiment, the Purine Derivatives of Formula (Ib) exist as amixture of a Purine Derivative of Formula (Ib′) and a Purine Derivativeof Formula (Ib″) wherein the amount of the Purine Derivative of Formula(Ib″) exceeds the amount of the Purine Derivative of Formula (Ib′).

In another embodiment, the Purine Derivatives of Formula (Ib) exist as aracemic mixture of a Purine Derivative of Formula (Ib′) and a PurineDerivative of Formula (Ib″).

In another embodiment, the Purine Derivatives of Formula (Ib) can existin the form of a single enantiomer, for example, that depicted by eitherformula (Ibb′) or (Ib″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ib).

A Purine Derivative of Formula (Ibb′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Ibb″) when group A of thePurine Derivative of Formula (Ibb′) is the same as group A of the PurineDerivative of Formula (Ibb″) and when group D of the Purine Derivativeof Formula (Ibb′) is the same as group D of the Purine Derivative ofFormula (Ibb″).

A Purine Derivative of Formula (Ibb″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Ibb′) when group A of thePurine Derivative of Formula (Ibb″) is the same as group A of the PurineDerivative of Formula (Ibb′) and when group D of the Purine Derivativeof Formula (Ibb″) is the same as group D of the Purine Derivative ofFormula (Ibb′).

In one embodiment, the Purine Derivatives of Formula (Ib) have theformula (Ibb′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ib), and wherein the PurineDerivatives of Formula (Ibb′) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (Ib) have theformula (Ibb″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ib), and wherein the PurineDerivatives of Formula (Ibb″) are substantially free of theircorresponding-opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (Ib) exist as amixture of a Purine Derivative of Formula (Ibb′) and a Purine Derivativeof Formula (Ibb″) wherein the amount of the Purine Derivative of Formula(Ibb′) exceeds the amount of the Purine Derivative of Formula (Ibb″).

In a further embodiment, the Purine Derivatives of Formula (Ib) exist asa mixture of a Purine Derivative of Formula (Ibb′) and a PurineDerivative of Formula (Ibb″) wherein the amount of the Purine Derivativeof Formula (Ibb″) exceeds the amount of the Purine Derivative of Formula(Ibb′).

In another embodiment, the Purine Derivatives of Formula (Ib) exist as aracemic mixture of a Purine Derivative of Formula (Ibb′) and a PurineDerivative of Formula (Ibb″).

A Purine Derivative of Formula (Ibb′) is the corresponding other anomerof a Purine Derivative of Formula (Ib′) when group A of the PurineDerivative of Formula (Ibb′) is the same as group A of the PurineDerivative of Formula (Ib′) and when group D of the Purine Derivative ofFormula (Ibb′) is the same as group D of the Purine Derivative ofFormula (Ib′).

A Purine Derivative of Formula (Ib′) is the corresponding other anomerof a Purine Derivative of Formula (Ibb′) when group A of the PurineDerivative of Formula (Ib′) is the same as group A of the PurineDerivative of Formula (Ibb′) and when group D of the Purine Derivativeof Formula (Ib′) is the same as group D of the Purine Derivative ofFormula (Ibb′).

A Purine Derivative of Formula (Ibb″) is the corresponding other anomerof a Purine Derivative of Formula (Ib″) when group A of the PurineDerivative of Formula (Ibb″) is the same as group A of the PurineDerivative of Formula (Ib″) and when group D of the Purine Derivative ofFormula (Ibb″) is the same as group D of the Purine Derivative ofFormula (Ib″).

A Purine Derivative of Formula (Ib″) is the corresponding other anomerof a Purine Derivative of Formula (Ibb″) when group A of the PurineDerivative of Formula (Ib″) is the same as group A of the PurineDerivative of Formula (Ibb″) and when group D of the Purine Derivativeof Formula (Ib″) is the same as group D of the Purine Derivative ofFormula (Ibb″).

In one embodiment, the Purine Derivatives of Formula (Ib) have theformula (Ibb′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ib), and wherein the PurineDerivatives of Formula (Ibb′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (Ib) have theformula (Ibb″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ib), and wherein the PurineDerivatives of Formula (Ibb″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (Ib) have theformula (Ib′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ib), and wherein the PurineDerivatives of Formula (Ib′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (Ib) have theformula (Ib″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ib), and wherein the PurineDerivatives of Formula (Ib″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (Ib) exist as amixture of a Purine Derivative of Formula (Ib′) and a Purine Derivativeof Formula (Ibb′) wherein the amount of the Purine Derivative of Formula(Ib′) exceeds the amount of the Purine Derivative of Formula (Ibb′).

In another embodiment, the Purine Derivatives of Formula (Ib) exist as amixture of a Purine Derivative of Formula (Ib′) and a Purine Derivativeof Formula (Ibb′) wherein the amount of the Purine Derivative of Formula(Ibb′) exceeds the amount of the Purine Derivative of Formula (Ib′).

In another embodiment, the Purine Derivatives of Formula (Ib) exist as aequal mixture of a Purine Derivative of Formula (Ib′) and a PurineDerivative of Formula (Ibb′).

In one embodiment, the Purine Derivatives of Formula (Ib) exist as amixture of a Purine Derivative of Formula (Ib″) and a Purine Derivativeof Formula (Ibb″) wherein the amount of the Purine Derivative of Formula(Ib″) exceeds the amount of the Purine Derivative of Formula (Ibb″).

In another embodiment, the Purine Derivatives of Formula (Ib) exist as amixture of a Purine Derivative of Formula (Ib″) and a Purine Derivativeof Formula (Ibb″) wherein the amount of the Purine Derivative of Formula(Ibb″) exceeds the amount of the Purine Derivative of Formula (Ib″).

In another embodiment, the Purine Derivatives of Formula (Ib) exist as aequal mixture of a Purine Derivative of Formula (Ib″) and a PurineDerivative of Formula (Ibb″).

Illustrative Purine Derivatives of Formula (Ib) include the compoundlisted below:

5.2.3 The Purine Derivatives of Formula (Ic)

As stated above, the present invention encompasses Purine Derivativeshaving the Formula (Ic):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ic), and A and B are trans with respect to each other; B and Care cis with respect to each other; and C and D are cis or trans withrespect to each other.

In one embodiment, R¹ is —H.

In another embodiment, R¹ is —C₁-C₁₀ alkyl.

In one embodiment, R¹ is -aryl or —(CH₂)_(n)-aryl.

In another embodiment, R¹ is —C₃-C₈ monocyclic cycloalkyl.

In a specific embodiment, R¹ is cyclopentyl.

In another embodiment, R¹ is —C₃-C₈ monocyclic cycloalkenyl.

In another embodiment, R¹ is —C₈-C₁₂ bicyclic cycloalkyl or —C₈-C₁₂bicyclic cycloalkenyl.

In still another embodiment, R¹ is —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkyl) or —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl).

In another embodiment, R¹ is -3- to 7-membered monocyclic heterocycle or-8- to 12-membered bicyclic heterocycle.

In another embodiment, R² is —NHR⁴, —OR⁴ or —SR⁴.

In a further embodiment, R² is —NHC(O)R⁴, —NHC(O)OR⁴ or —NHC(O)NHR⁴.

In another embodiment, R² is —NHNHC(O)R⁴, —NHNHC(O)OR⁴ or —NHNHC(O)NHR⁴.In one embodiment, R⁵ is —C(O)O(C₁-C₁₀ alkyl).

In another embodiment, R⁵ is —C(O)NH(C₁-C₁₀ alkyl), —C(O)N(C₁-C₁₀alkyl)₂ or —C(O)NH-aryl.

In another embodiment, R⁵ is —CH(NH₂)NH₂ or —CH(NH₂)NH(C₁-C₁₀ alkyl).

In one embodiment, C and D are cis with respect to each other.

In another embodiment, C and D are trans with respect to each other.

The present invention also provides compositions comprising an effectiveamount of a Purine Derivative of Formula (Ic) and a physiologicallyacceptable carrier or vehicle.

The invention further provides Purine Derivatives of Formula (Ic) thatare in isolated and purified form.

The invention still further provides methods for treating or preventinga Condition, comprising administering an effective amount of a PurineDerivative of Formula (Ic) to an animal in need thereof.

The invention further provides methods for reducing an animal's rate ofmetabolism, comprising administering an effective amount of a PurineDerivative of Formula (Ic) to an animal in need thereof.

The invention further provides methods protecting an animal's heartagainst myocardial damage during cardioplegia, comprising administeringan effective amount of a Purine Derivative of Formula (Ic) to an animalin need thereof.

The Purine Derivatives of Formula (Ic) can exist in the form of a singleenantiomer, for example, that depicted by either the Formula (Ic′) orFormula (Ic″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ic).

A Purine Derivative of Formula (Ic′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Ic″) when group A of thePurine Derivative of Formula (Ic′) is the same as group A of the PurineDerivative of Formula (Ic″) and when group D of the Purine Derivative ofFormula (Ic′) is the same as group D of the Purine Derivative of Formula(Ic″).

A Purine Derivative of Formula (Ic″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Ic′) when group A of thePurine Derivatives of Formula (Ic″) is the same as group A of the PurineDerivative of Formula (Ic′) and when group D of the Purine Derivative ofFormula (Ic″) is the same as group D of the Purine Derivative of Formula(Ic′).

In one embodiment, the Purine Derivatives of Formula (Ic) have theformula (Ic′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ic), and wherein the PurineDerivatives of Formula (Ic′) are substantially free of theircorresponding enantiomer, represented by Formula (Ic″).

In another embodiment, the Purine Derivatives of Formula (Ic) have theformula (Ic″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ic), and wherein the PurineDerivatives of Formula (Ic″) are substantially free of theircorresponding enantiomer, represented by Formula (Ic′).

In one embodiment, the Purine Derivatives of Formula (Ic) exist as amixture of a Purine Derivative of Formula (Ic′) and a Purine Derivativeof Formula (Ic″) wherein the amount of the Purine Derivative of Formula(Ic′) exceeds the amount of the Purine Derivative of Formula (Ic″).

In another embodiment, the Purine Derivatives of Formula (Ic) exist as amixture of a Purine Derivative of Formula (Ic′) and a Purine Derivativeof Formula (Ic″) wherein the amount of the Purine Derivative of Formula(Ic″) exceeds the amount of the Purine Derivative of Formula (Ic′).

In another embodiment, the Purine Derivatives of Formula (Ic) exist as aracemic mixture of a Purine Derivative of Formula (Ic′) and a PurineDerivative of Formula (Ic″).

In another embodiment, the Purine Derivatives of Formula (Ic) can existin the form of a single enantiomer, for example, that depicted by eitherformula (Icc′) or (Icc″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ic).

A Purine Derivative of Formula (Icc′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Icc″) when group A of thePurine Derivative of Formula (Icc′) is the same as group A of the PurineDerivative of Formula (Icc″) and when group D of the Purine Derivativeof Formula (Icc′) is the same as group D of the Purine Derivative ofFormula (Icc″).

A Purine Derivative of Formula (Icc″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Icc′) when group A of thePurine Derivative of Formula (Icc″) is the same as group A of the PurineDerivative of Formula (Icc′) and when group D of the Purine Derivativeof Formula (Icc″) is the same as group D of the Purine Derivative ofFormula (Icc′).

In one embodiment, the Purine Derivatives of Formula (Ic) have theformula (Icc′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ic), and wherein the PurineDerivatives of Formula (Icc′) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (Ic) have theformula (Icc″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ic), and wherein the PurineDerivatives of Formula (Icc″) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (Ic) exist as amixture of a Purine Derivative of Formula (Icc′) and a Purine Derivativeof Formula (Icc″) wherein the amount of the Purine Derivative of Formula(Icc′) exceeds the amount of the Purine Derivative of Formula (Icc″).

In a further embodiment, the Purine Derivatives of Formula (Ic) exist asa mixture of a Purine Derivative of Formula (Icc′) and a PurineDerivative of Formula (Icc″) wherein the amount of the Purine Derivativeof Formula (Icc″) exceeds the amount of the Purine Derivative of Formula(Icc′).

In another embodiment, the Purine Derivatives of Formula (Ic) exist as aracemic mixture of a Purine Derivative of Formula (Icc′) and a PurineDerivative of Formula (Icc″).

A Purine Derivative of Formula (Icc′) is the corresponding other anomerof a Purine Derivative of Formula (Ic′) when group A of the PurineDerivative of Formula (Icc′) is the same as group A of the PurineDerivative of Formula (Ic′) and when group D of the Purine Derivative ofFormula (Icc′) is the same as group D of the Purine Derivative ofFormula (Ic′).

A Purine Derivative of Formula (Ic′) is the corresponding other anomerof a Purine Derivative of Formula (Icc′) when group A of the PurineDerivative of Formula (Ic′) is the same as group A of the PurineDerivative of Formula (Icc′) and when group D of the Purine Derivativeof Formula (Ic′) is the same as group D of the Purine Derivative ofFormula (Icc′).

A Purine Derivative of Formula (Icc″) is the corresponding other anomerof a Purine Derivative of Formula (Ic″) when group A of the PurineDerivative of Formula (Icc″) is the same as group A of the PurineDerivative of Formula (Ic″) and when group D of the Purine Derivative ofFormula (Icc″) is the same as group D of the Purine Derivative ofFormula (Ic″).

A Purine Derivative of Formula (Ic″) is the corresponding other anomerof a Purine Derivative of Formula (Icc″) when group A of the PurineDerivative of Formula (Ic″) is the same as group A of the PurineDerivative of Formula (Icc″) and when group D of the Purine Derivativeof Formula (Ic″) is the same as group D of the Purine Derivative ofFormula (Icc″).

In one embodiment, the Purine Derivatives of Formula (Ic) have theformula (Icc′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ic), and wherein the PurineDerivatives of Formula (Icc′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (Ic) have theformula (Icc″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ic), and wherein the PurineDerivatives of Formula (Icc″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (Ic) have theformula (Ic′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ic), and wherein the PurineDerivatives of Formula (Ic′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (Ic) have theformula (Ic″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ic), and wherein the PurineDerivatives of Formula (Ic″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (Ic) exist as amixture of a Purine Derivative of Formula (Ic′) and a Purine Derivativeof Formula (Icc′) wherein the amount of the Purine Derivative of Formula(Ic′) exceeds the amount of the Purine Derivative of Formula (Icc′).

In another embodiment, the Purine Derivatives of Formula (Ic) exist as amixture of a Purine Derivative of Formula (Ic′) and a Purine Derivativeof Formula (Icc′) wherein the amount of the Purine Derivative of Formula(Icc′) exceeds the amount of the Purine Derivative of Formula (Ic′).

In another embodiment, the Purine Derivatives of Formula (Ic) exist as aequal mixture of a Purine Derivative of Formula (Ic′) and a PurineDerivative of Formula (Icc′).

In one embodiment, the Purine Derivatives of Formula (Ic) exist as amixture of a Purine Derivative of Formula (Ic″) and a Purine Derivativeof Formula (Icc″) wherein the amount of the Purine Derivative of Formula(Ic″) exceeds the amount of the Purine Derivative of Formula (Icc″).

In another embodiment, the Purine Derivatives of Formula (Ic) exist as amixture of a Purine Derivative of Formula (Ic″) and a Purine Derivativeof Formula (Icc″) wherein the amount of the Purine Derivative of Formula(Icc″) exceeds the amount of the Purine Derivative of Formula (Ic″).

In another embodiment, the Purine Derivatives of Formula (Ic) exist as aequal mixture of a Purine Derivative of Formula (Ic″) and a PurineDerivative of Formula (Icc″).

5.2.4 The Purine Derivatives of Formula (Id)

As stated above, the present invention encompasses Purine Derivativeshaving the Formula (Id):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Id), and A and B are trans with respect to each other; B and Care cis with respect to each other; and C and D are cis or trans withrespect to each other.

In one embodiment, R¹ is —H.

In another embodiment, R¹ is —C₁-C₁₀ alkyl.

In one embodiment, R¹ is -aryl or —(CH₂)_(n)-aryl.

In another embodiment, R¹ is —C₃-C₈ monocyclic cycloalkyl.

In a specific embodiment, R¹ is cyclopentyl.

In another embodiment, R¹ is —C₃-C₈ monocyclic cycloalkenyl.

In another embodiment, R¹ is —C₈-C₁₂ bicyclic cycloalkyl or —C₈-C₁₂bicyclic cycloalkenyl.

In still another embodiment, R¹ is —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkyl) or —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl).

In another embodiment, R¹ is -3- to 7-membered monocyclic heterocycle or-8- to 12-membered bicyclic heterocycle.

In one embodiment, R² is —H.

In one embodiment, R² is -halo.

In a specific embodiment, R² is —Cl.

In another embodiment, R² is —N.

In another embodiment, R² is —NHR⁴, —OR⁴ or —SR⁴.

In a further embodiment, R² is —NHC(O)R⁴, —NHC(O)OR⁴ or —NHC(O)NHR⁴.

In another embodiment, R² is —NHNHC(O)R⁴, —NHNHC(O)OR⁴ or —NHNHC(O)NHR⁴.

In yet another embodiment, R² is —NH—N═C(R⁶)R⁷.

In one embodiment, R³ is —CH₂ONO.

In another embodiment, R³ is —CH₂OSO₃H.

In one embodiment, C and D are cis with respect to each other.

In another embodiment, C and D are trans with respect to each other.

The present invention also provides compositions comprising an effectiveamount of a Purine Derivative of Formula (Id) and a physiologicallyacceptable carrier or vehicle.

The invention further provides Purine Derivatives of Formula (Id) thatare in isolated and purified form.

The invention still further provides methods for treating or preventinga Condition, comprising administering an effective amount of a PurineDerivative of Formula (Id) to an animal in need thereof.

The invention further provides methods for reducing an animal's rate ofmetabolism, comprising administering an effective amount of a PurineDerivative of Formula (Id) to an animal in need thereof.

The invention further provides methods protecting an animal's heartagainst myocardial damage during cardioplegia, comprising administeringan effective amount of a Purine Derivative of Formula (Id) to an animalin need thereof.

The Purine Derivatives of Formula (Id) can exist in the form of a singleenantiomer, for example, that depicted by either the Formula (Id′) orFormula (Id″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Id).

A Purine Derivative of Formula (Id′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Id″) when group A of thePurine Derivative of Formula (Id′) is the same as group A of the PurineDerivative of Formula (Id″) and when group D of the Purine Derivative ofFormula (Id′) is the same as group D of the Purine Derivative of Formula(Id″).

A Purine Derivative of Formula (Id″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Id′) when group A of thePurine Derivatives of Formula (Id″) is the same as group A of the PurineDerivative of Formula (Id′) and when group D of the Purine Derivative ofFormula (Id″) is the same as group D of the Purine Derivative of Formula(Id′).

In one embodiment, the Purine Derivatives of Formula (Id) have theformula (Id′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Id), and wherein the PurineDerivatives of Formula (Id′) are substantially free of theircorresponding enantiomer, represented by Formula (Id″).

In another embodiment, the Purine Derivatives of Formula (Id) have theformula (Id″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Id), and wherein the PurineDerivatives of Formula (Id″) are substantially free of theircorresponding enantiomer, represented by Formula (Id′).

In one embodiment, the Purine Derivatives of Formula (Id) exist as amixture of a Purine Derivative of Formula (Id′) and a Purine Derivativeof Formula (Id″) wherein the amount of the Purine Derivative of Formula(Id′) exceeds the amount of the Purine Derivative of Formula (Id″).

In another embodiment, the Purine Derivatives of Formula (Id) exist as amixture of a Purine Derivative of Formula (Id′) and a Purine Derivativeof Formula (Id″) wherein the amount of the Purine Derivative of Formula(Id″) exceeds the amount of the Purine Derivative of Formula (Id′).

In another embodiment, the Purine Derivatives of Formula (Id) exist as aracemic mixture of a Purine Derivative of Formula (Id′) and a PurineDerivative of Formula (Id″).

In another embodiment, the Purine Derivatives of Formula (Id) can existin the form of a single enantiomer, for example, that depicted by eitherformula (Idd′) or (Idd″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Id).

A Purine Derivative of Formula (Idd′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Idd″) when group A of thePurine Derivative of Formula (Idd′) is the same as group A of the PurineDerivative of Formula (Idd″) and when group D of the Purine Derivativeof Formula (Idd′) is the same as group D of the Purine Derivative ofFormula (Idd″).

A Purine Derivative of Formula (Idd″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Idd′) when group A of thePurine Derivative of Formula (Idd″) is the same as group A of the PurineDerivative of Formula (Idd′) and when group D of the Purine Derivativeof Formula (Idd″) is the same as group D of the Purine Derivative ofFormula (Idd′).

In one embodiment, the Purine Derivatives of Formula (Id) have theformula (Idd′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Id), and wherein the PurineDerivatives of Formula (Idd′) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (Id) have theformula (Idd″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Id), and wherein the PurineDerivatives of Formula (Idd″) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (Id) exist as amixture of a Purine Derivative of Formula (Idd′) and a Purine Derivativeof Formula (Idd″) wherein the amount of the Purine Derivative of Formula(Idd′) exceeds the amount of the Purine Derivative of Formula (Idd″).

In a further embodiment, the Purine Derivatives of Formula (Id) exist asa mixture of a Purine Derivative of Formula (Idd′) and a PurineDerivative of Formula (Idd″) wherein the amount of the Purine Derivativeof Formula (Idd″) exceeds the amount of the Purine Derivative of Formula(Idd′).

In another embodiment, the Purine Derivatives of Formula (Id) exist as aracemic mixture of a Purine Derivative of Formula (Idd′) and a PurineDerivative of Formula (Idd″).

A Purine Derivative of Formula (Idd′) is the corresponding other anomerof a Purine Derivative of Formula (Id′) when group A of the PurineDerivative of Formula (Idd′) is the same as group A of the PurineDerivative of Formula (Ib′) and when group D of the Purine Derivative ofFormula (Idd′) is the same as group D of the Purine Derivative ofFormula (Id′).

A Purine Derivative of Formula (Id′) is the corresponding other anomerof a Purine Derivative of Formula (Idd′) when group A of the PurineDerivative of Formula (Id′) is the same as group A of the PurineDerivative of Formula (Idd′) and when group D of the Purine Derivativeof Formula (Id′) is the same as group D of the Purine Derivative ofFormula (Idd′).

A Purine Derivative of Formula (Idd″) is the corresponding other anomerof a Purine Derivative of Formula (Id″) when group A of the PurineDerivative of Formula (Idd″) is the same as group A of the PurineDerivative of Formula (Id″) and when group D of the Purine Derivative ofFormula (Idd″) is the same as group D of the Purine Derivative ofFormula (Id″).

A Purine Derivative of Formula (Id″) is the corresponding other anomerof a Purine Derivative of Formula (Idd″) when group A of the PurineDerivative of Formula (Id″) is the same as group A of the PurineDerivative of Formula (Idd″) and when group D of the Purine Derivativeof Formula (Id″) is the same as group D of the Purine Derivative ofFormula (Idd″).

In one embodiment, the Purine Derivatives of Formula (Id) have theformula (Idd′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Id), and wherein the PurineDerivatives of Formula (Idd′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (Id) have theformula (Idd″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Id), and wherein the PurineDerivatives of Formula (Idd″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (Id) have theformula (Id′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Id), and wherein the PurineDerivatives of Formula (Id′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (Id) have theformula (Id″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Id), and wherein the PurineDerivatives of Formula (Id″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (Id) exist as amixture of a Purine Derivative of Formula (Id′) and a Purine Derivativeof Formula (Idd′) wherein the amount of the Purine Derivative of Formula(Id′) exceeds the amount of the Purine Derivative of Formula (Idd′).

In another embodiment, the Purine Derivatives of Formula (Id) exist as amixture of a Purine Derivative of Formula (Id′) and a Purine Derivativeof Formula (Idd′) wherein the amount of the Purine Derivative of Formula(Idd′) exceeds the amount of the Purine Derivative of Formula (Id′).

In another embodiment, the Purine Derivatives of Formula (Id) exist as aequal mixture of a Purine Derivative of Formula (Id′) and a PurineDerivative of Formula (Idd′).

In one embodiment, the Purine Derivatives of Formula (Id) exist as amixture of a Purine Derivative of Formula (Id″) and a Purine Derivativeof Formula (Idd″) wherein the amount of the Purine Derivative of Formula(Id″) exceeds the amount of the Purine Derivative of Formula (Idd″).

In another embodiment, the Purine Derivatives of Formula (Id) exist as amixture of a Purine Derivative of Formula (Id″) and a Purine Derivativeof Formula (Idd″) wherein the amount of the Purine Derivative of Formula(Idd″) exceeds the amount of the Purine Derivative of Formula (Id″).

In another embodiment, the Purine Derivatives of Formula (Id) exist as aequal mixture of a Purine Derivative of Formula (Id″) and a PurineDerivative of Formula (Idd″)

Illustrative Purine Derivatives of Formula (Id) include the compoundslisted below:

and pharmaceutically acceptable salts thereof.

In one embodiment, compound 23 is in the form of its sodium salt.

In another embodiment, compound 24 is in the form of its sodium salt.

5.2.5 The Purine Derivatives of Formula (Ie)

As stated above, the present invention encompasses Purine Derivativeshaving the Formula (Ie):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ie), and A and B are trans with respect to each other; B and Care cis with respect to each other; and C and D are cis or trans withrespect to each other.

In one embodiment, R¹ is —(CH₂)_(n)-aryl.

In another embodiment, R¹ is —C₃-C₈ monocyclic cycloalkyl.

In a specific embodiment, R¹ is cyclopentyl.

In another embodiment, R¹ is —C₃-C₈ monocyclic cycloalkenyl.

In another embodiment, R¹ is —C₈-C₁₂ bicyclic cycloalkyl or —C₈-C₁₂bicyclic cycloalkenyl.

In still another embodiment, R¹ is —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkyl) or —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl).

In another embodiment, R¹ is -3- to 7-membered monocyclic heterocycle or-8- to 12-membered bicyclic heterocycle.

In one embodiment, R² is -halo.

In a specific embodiment, R² is —Cl.

In another embodiment, R² is —CN.

In another embodiment, R² is —NHR⁴, —OR⁴ or —R⁴.

In a further embodiment, R² is —NHC(O)R⁴, —NHC(O)OR⁴ or —NHC(O)NHR⁴.

In another embodiment, R² is —NHNHC(O)R⁴, —NHNHC(O)OR⁴ or —NHNHC(O)NHR⁴.

In yet another embodiment, R² is —NH—N═C(R⁶)R⁷.

In one embodiment, C and D are cis with respect to each other.

In another embodiment, C and D are trans with respect to each other.

The present invention also provides compositions comprising an effectiveamount of a Purine Derivative of Formula (Ie) and a physiologicallyacceptable carrier or vehicle.

The invention further provides Purine Derivatives of Formula (Ie) thatare in isolated and purified form.

The invention still further provides methods for treating or preventinga Condition, comprising administering an effective amount of a PurineDerivative of Formula (Ie) to an animal in need thereof.

The invention further provides methods for reducing an animal's rate ofmetabolism, comprising administering an effective amount of a PurineDerivative of Formula (Ie) to an animal in need thereof.

The invention further provides methods protecting an animal's heartagainst myocardial damage during cardioplegia, comprising administeringan effective amount of a Purine Derivative of Formula (Ie) to an animalin need thereof.

The Purine Derivatives of Formula (Ie) can exist in the form of a singleenantiomer, for example, that depicted by either the Formula (Ie′) orFormula (Ie″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ie).

A Purine Derivative of Formula (Ie′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Ie″) when group A of thePurine Derivative of Formula (Ie′) is the same as group A of the PurineDerivative of Formula (Ie″) and when group D of the Purine Derivative ofFormula (Ie′) is the same as group D of the Purine Derivative of Formula(Ie″).

A Purine Derivative of Formula (Ie″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Ie′) when group A of thePurine Derivatives of Formula (Ie″) is the same as group A of the PurineDerivative of Formula (Ie′) and when group D of the Purine Derivative ofFormula (Ie″) is the same as group D of the Purine Derivative of Formula(Ie′).

In one embodiment, the Purine Derivatives of Formula (Ie) have theformula (Ie′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ie), and wherein the PurineDerivatives of Formula (Ie′) are substantially free of theircorresponding enantiomer, represented by Formula (Ie″).

In another embodiment, the Purine Derivatives of Formula (Ie) have theformula (Ie″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ie), and wherein the PurineDerivatives of Formula (Ie″) are substantially free of theircorresponding enantiomer, represented by Formula (Ie′).

In one embodiment, the Purine Derivatives of Formula (Ie) exist as amixture of a Purine Derivative of Formula (Ie′) and a Purine Derivativeof Formula (Ie″) wherein the amount of the Purine Derivative of Formula(Ie′) exceeds the amount of the Purine Derivative of Formula (Ie″).

In another embodiment, the Purine Derivatives of Formula (Ie) exist as amixture of a Purine Derivative of Formula (Ie′) and a Purine Derivativeof Formula (Ie″) wherein the amount of the Purine Derivative of Formula(Ie″) exceeds the amount of the Purine Derivative of Formula (Ie′).

In another embodiment, the Purine Derivatives of Formula (Ie) exist as aracemic mixture of a Purine Derivative of Formula (Ie′) and a PurineDerivative of Formula (Ie″).

In another embodiment, the Purine Derivatives of Formula (Ie) can existin the form of a single enantiomer, for example, that depicted by eitherformula (Iee′) or (Iee″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ie).

A Purine Derivative of Formula (Iee′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Iee″) when group A of thePurine Derivative of Formula (Iee′) is the same as group A of the PurineDerivative of Formula (Iee″) and when group D of the Purine Derivativeof Formula (Iee′) is the same as group D of the Purine Derivative ofFormula (Iee″).

A Purine Derivative of Formula (Iee″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Iee′) when group A of thePurine Derivative of Formula (Iee″) is the same as group A of the PurineDerivative of Formula (Iee′) and when group D of the Purine Derivativeof Formula (Iee″) is the same as group D of the Purine Derivative ofFormula (Iee′).

In one embodiment, the Purine Derivatives of Formula (Ie) have theformula (Iee′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ie), and wherein the PurineDerivatives of Formula (Iee′) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (Ie) have theformula (Iee″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ie), and wherein the PurineDerivatives of Formula (Iee″) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (Ie) exist as amixture of a Purine Derivative of Formula (Iee′) and a Purine Derivativeof Formula (Iee″) wherein the amount of the Purine Derivative of Formula(Iee′) exceeds the amount of the Purine Derivative of Formula (Iee″).

In a further embodiment, the Purine Derivatives of Formula (Ie) exist asa mixture of a Purine Derivative of Formula (Iee′) and a PurineDerivative of Formula (Iee″) wherein the amount of the Purine Derivativeof Formula (Iee″) exceeds the amount of the Purine Derivative of Formula(Iee′).

In another embodiment, the Purine Derivatives of Formula (Ie) exist as aracemic mixture of a Purine Derivative of Formula (Iee′) and a PurineDerivative of Formula (Iee″).

A Purine Derivative of Formula (Iee′) is the corresponding other anomerof a Purine Derivative of Formula (Ie′) when group A of the PurineDerivative of Formula (Iee′) is the same as group A of the PurineDerivative of Formula (Ie′) and when group D of the Purine Derivative ofFormula (Iee′) is the same as group D of the Purine Derivative ofFormula (Ie′).

A Purine Derivative of Formula (Ie′) is the corresponding other anomerof a Purine Derivative of Formula (Iee′) when group A of the PurineDerivative of Formula (Ie′) is the same as group A of the PurineDerivative of Formula (Iee′) and when group D of the Purine Derivativeof Formula (Ie′) is the same as group D of the Purine Derivative ofFormula (Iee′).

A Purine Derivative of Formula (Iee″) is the corresponding other anomerof a Purine Derivative of Formula (Ie″) when group A of the PurineDerivative of Formula (Iee″) is the same as group A of the PurineDerivative of Formula (Ie″) and when group D of the Purine Derivative ofFormula (Iee″) is the same as group D of the Purine Derivative ofFormula (Ie″).

A Purine Derivative of Formula (Ie″) is the corresponding other anomerof a Purine Derivative of Formula (Iee″) when group A of the PurineDerivative of Formula (Ie″) is the same as group A of the PurineDerivative of Formula (Iee″) and when group D of the Purine Derivativeof Formula (Ie″) is the same as group D of the Purine Derivative ofFormula (Iee″).

In one embodiment, the Purine Derivatives of Formula (Ie) have theformula (Iee′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ie), and wherein the PurineDerivatives of Formula (Iee′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (Ie) have theformula (Iee″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ie), and wherein the PurineDerivatives of Formula (Iee″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (Ie) have theformula (Ie′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ie), and wherein the PurineDerivatives of Formula (Ie′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (Ie) have theformula (Ie″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ie), and wherein the PurineDerivatives of Formula (Ie″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (Ie) exist as amixture of a Purine Derivative of Formula (Ie′) and a Purine Derivativeof Formula (Iee′) wherein the amount of the Purine Derivative of Formula(Ie′) exceeds the amount of the Purine Derivative of Formula (Iee′).

In another embodiment, the Purine Derivatives of Formula (Ie) exist as amixture of a Purine Derivative of Formula (Ie′) and a Purine Derivativeof Formula (Iee′) wherein the amount of the Purine Derivative of Formula(Iee′) exceeds the amount of the Purine Derivative of Formula (Ie′).

In another embodiment, the Purine Derivatives of Formula (Ie) exist as aequal mixture of a Purine Derivative of Formula (Ie′) and a PurineDerivative of Formula (Iee′).

In one embodiment, the Purine Derivatives of Formula (Ie) exist as amixture of a Purine Derivative of Formula (Ie″) and a Purine Derivativeof Formula (Iee″) wherein the amount of the Purine Derivative of Formula(Ie″) exceeds the amount of the Purine Derivative of Formula (Iee″).

In another embodiment, the Purine Derivatives of Formula (Ie) exist as amixture of a Purine Derivative of Formula (Ie″) and a Purine Derivativeof Formula (Iee″) wherein the amount of the Purine Derivative of Formula(Iee″) exceeds the amount of the Purine Derivative of Formula (Ie″).

In another embodiment, the Purine Derivatives of Formula (Ie) exist as aequal mixture of a Purine Derivative of Formula (Ie″) and a PurineDerivative of Formula (Iee″).

5.2.6 The Purine Derivatives of Formula (If)

As stated above, the present invention encompasses Purine Derivativeshaving the Formula (If):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (If), and A and B are trans with respect to each other; B and Care cis with respect to each other; and C and D are cis or trans withrespect to each other.

In one embodiment, R¹ is —C₅-C₆ monocyclic cycloalkyl.

In another embodiment, R¹ is cyclopentyl.

In one embodiment, R² is —H

In another embodiment R² is -halo.

In another embodiment, R² is —Cl.

In one embodiment, C and D are cis with respect to each other.

In another embodiment, C and D are trans with respect to each other.

The present invention also provides compositions comprising an effectiveamount of a Purine Derivative of Formula (If) and a physiologicallyacceptable carrier or vehicle.

The invention further provides Purine Derivatives of Formula (If) thatare in isolated and purified form.

The invention still further provides methods for treating or preventinga Condition, comprising administering an effective amount of a PurineDerivative of Formula (If) to an animal in need thereof.

The invention further provides methods for reducing an animal's rate ofmetabolism, comprising administering an effective amount of a PurineDerivative of Formula (If) to an animal in need thereof.

The invention further provides methods protecting an animal's heartagainst myocardial damage during cardioplegia, comprising administeringan effective amount of a Purine Derivative of Formula (If) to an animalin need thereof.

The Purine Derivatives of Formula (If) can exist in the form of a singleenantiomer, for example, that depicted by either the Formula (If′) orFormula (If″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (If).

A Purine Derivative of Formula (If′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (If″) when group A of thePurine Derivative of Formula (If′) is the same as group A of the PurineDerivative of Formula (If″) and when group D of the Purine Derivative ofFormula (If′) is the same as group D of the Purine Derivative of Formula(If″).

A Purine Derivative of Formula (If″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (If′) when group A of thePurine Derivatives of Formula (If″) is the same as group A of the PurineDerivative of Formula (If′) and when group D of the Purine Derivative ofFormula (If″) is the same as group D of the Purine Derivative of Formula(If′).

In one embodiment, the Purine Derivatives of Formula (If) have theformula (If′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (If), and wherein the PurineDerivatives of Formula (If′) are substantially free of theircorresponding enantiomer, represented by Formula (If″).

In another embodiment, the Purine Derivatives of Formula (If) have theformula (If″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (If), and wherein the PurineDerivatives of Formula (If″) are substantially free of theircorresponding enantiomer, represented by Formula (If′).

In one embodiment, the Purine Derivatives of Formula (If) exist as amixture of a Purine Derivative of Formula (If′) and a Purine Derivativeof Formula (If″) wherein the amount of the Purine Derivative of Formula(If′) exceeds the amount of the Purine Derivative of Formula (If″).

In another embodiment, the Purine Derivatives of Formula (If) exist as amixture of a Purine Derivative of Formula (If′) and a Purine Derivativeof Formula (If″) wherein the amount of the Purine Derivative of Formula(If″) exceeds the amount of the Purine Derivative of Formula (If′).

In another embodiment, the Purine Derivatives of Formula (If) exist as aracemic mixture of a Purine Derivative of Formula (If′) and a PurineDerivative of Formula (If″).

In another embodiment, the Purine Derivatives of Formula (If) can existin the form of a single enantiomer, for example, that depicted by eitherformula (Iff″) or (Iff″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (If).

A Purine Derivative of Formula (Iff″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Iff″) when group A of thePurine Derivative of Formula (Iff″) is the same as group A of the PurineDerivative of Formula (Iff″) and when group D of the Purine Derivativeof Formula (If′) is the same as group D of the Purine Derivative ofFormula (If″).

A Purine Derivative of Formula (Iff″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (If′) when group A of thePurine Derivative of Formula (Iff″) is the same as group A of the PurineDerivative of Formula (Iff′) and when group D of the Purine Derivativeof Formula (If″) is the same as group D of the Purine Derivative ofFormula (Iff′).

In one embodiment, the Purine Derivatives of Formula (If) have theformula (Iff′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (If), and wherein the PurineDerivatives of Formula (Iff′) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine. Derivatives of Formula (If) have theformula (Iff″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (If), and wherein the PurineDerivatives of Formula (Iff″) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (If) exist as amixture of a Purine Derivative of Formula (Iff′) and a Purine Derivativeof Formula (Iff″) wherein the amount of the Purine Derivative of Formula(Iff′) exceeds the amount of the Purine Derivative of Formula (Iff″).

In a further embodiment, the Purine Derivatives of Formula (If) exist asa mixture of a Purine Derivative of Formula (If′) and a PurineDerivative of Formula (Iff″) wherein the amount of the Purine Derivativeof Formula (Iff″) exceeds the amount of the Purine Derivative of Formula(Iff′).

In another embodiment, the Purine Derivatives of Formula (If) exist as aracemic mixture of a Purine Derivative of Formula (If′) and a PurineDerivative of Formula (Iff″).

A Purine Derivative of Formula (Iff′) is the corresponding other anomerof a Purine Derivative of Formula (If′) when group A of the PurineDerivative of Formula (Iff′) is the same as group A of the PurineDerivative of Formula (If′) and when group D of the Purine Derivative ofFormula (If′) is the same as group D of the Purine Derivative of Formula(If′).

A Purine Derivative of Formula (If′) is the corresponding other anomerof a Purine Derivative of Formula (Iff′) when group A of the PurineDerivative of Formula (If′) is the same as group A of the PurineDerivative of Formula (Iff′) and when group D of the Purine Derivativeof Formula (If′) is the same as group D of the Purine Derivative ofFormula (Iff′).

A Purine Derivative of Formula (Iff″) is the corresponding other anomerof a Purine Derivative of Formula (If″) when group A of the PurineDerivative of Formula (Iff″) is the same as group A of the PurineDerivative of Formula (If″) and when group D of the Purine Derivative ofFormula (Iff″) is the same as group D of the Purine Derivative ofFormula (If″).

A Purine Derivative of Formula (If″) is the corresponding other anomerof a Purine Derivative of Formula (Iff″) when group A of the PurineDerivative of Formula (If″) is the same as group A of the PurineDerivative of Formula (Iff″) and when group D of the Purine Derivativeof Formula (If″) is the same as group D of the Purine Derivative ofFormula (Iff″).

In one embodiment, the Purine Derivatives of Formula (If) have theformula (Iff′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (If), and wherein the PurineDerivatives of Formula (Iff′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (If) have theformula (Iff″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (If), and wherein the PurineDerivatives of Formula (Iff″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (If) have theformula (If′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (If), and wherein the PurineDerivatives of Formula (If′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (If) have theformula (If″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (If), and wherein the PurineDerivatives of Formula (If″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (If) exist as amixture of a Purine Derivative of Formula (If′) and a Purine Derivativeof Formula (Iff′) wherein the amount of the Purine Derivative of Formula(If′) exceeds the amount of the Purine Derivative of Formula (Iff′).

In another embodiment, the Purine Derivatives of Formula (If) exist as amixture of a Purine Derivative of Formula (If′) and a Purine Derivativeof Formula (Iff′) wherein the amount of the Purine Derivative of Formula(Iff′) exceeds the amount of the Purine Derivative of Formula (If′).

In another embodiment, the Purine Derivatives of Formula (If) exist as aequal mixture of a Purine Derivative of Formula (If′) and a PurineDerivative of Formula (Iff′).

In one embodiment, the Purine Derivatives of Formula (If) exist as amixture of a Purine Derivative of Formula (If″) and a Purine Derivativeof Formula (Iff″) wherein the amount of the Purine Derivative of Formula(If″) exceeds the amount of the Purine Derivative of Formula (Iff″).

In another embodiment, the Purine Derivatives of Formula (If) exist as amixture of a Purine Derivative of Formula (If″) and a Purine Derivativeof Formula (Iff″) wherein the amount of the Purine Derivative of Formula(Iff″) exceeds the amount of the Purine Derivative of Formula (If″).

In another embodiment, the Purine Derivatives of Formula (If) exist as aequal mixture of a Purine Derivative of Formula (If″) and a PurineDerivative of Formula (Iff″).

Illustrative Purine Derivatives of Formula (If) include the compoundslisted below:

and pharmaceutically acceptable salts thereof.

5.2.7 The Purine Derivatives of Formula (Ig)

As stated above, the present invention encompasses Purine Derivativeshaving the Formula (Ig):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ig), and A and B are trans with respect to each other; B and Care cis with respect to each other; and C and D are cis or trans withrespect to each other.

In one embodiment, R² is —H

In another embodiment R² is -halo.

In a specific embodiment, R² is —Cl.

In one embodiment, C and D are cis with respect to each other.

In another embodiment, C and D are trans with respect to each other.

The present invention also provides compositions comprising an effectiveamount of a Purine Derivative of Formula (Ig) and a physiologicallyacceptable carrier or vehicle.

The invention further provides Purine Derivatives of Formula (Ig) thatare in isolated and purified form.

The invention still further provides methods for treating or preventinga Condition, comprising administering an effective amount of a PurineDerivative of Formula (Ig) to an animal in need thereof.

The invention further provides methods for reducing an animal's rate ofmetabolism, comprising administering an effective amount of a PurineDerivative of Formula (Ig) to an animal in need thereof.

The invention further provides methods protecting an animal's heartagainst myocardial damage during cardioplegia, comprising administeringan effective amount of a Purine Derivative of Formula (Ig) to an animalin need thereof.

The Purine Derivatives of Formula (Ig) can exist in the form of a singleenantiomer, for example, that depicted by either the Formula (Ig′) orFormula (Ig″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ig).

A Purine Derivative of Formula (Ig′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Ig″) when group A of thePurine Derivative of Formula (Ig′) is the same as group A of the PurineDerivative of Formula (Ig″) and when group D of the Purine Derivative ofFormula (Ig′) is the same as group D of the Purine Derivative of Formula(Ig″).

A Purine Derivative of Formula (Ig″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Ig′) when group A of thePurine Derivatives of Formula (Ig″) is the same as group A of the PurineDerivative of Formula (Ig′) and when group D of the Purine Derivative ofFormula (Ig″) is the same as group D of the Purine Derivative of Formula(Ig′).

In one embodiment, the Purine Derivatives of Formula (Ig) have theformula (Ig′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ig), and wherein the PurineDerivatives of Formula (Ig′) are substantially free of theircorresponding enantiomer, represented by Formula (Ig″).

In another embodiment, the Purine Derivatives of Formula (Ig) have theformula (Ig″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ig), and wherein the PurineDerivatives of Formula (Ig″) are substantially free of theircorresponding enantiomer, represented by Formula (Ig′).

In one embodiment, the Purine Derivatives of Formula (Ig) exist as amixture of a Purine Derivative of Formula (Ig′) and a Purine Derivativeof Formula (Ig″) wherein the amount of the Purine Derivative of Formula(Ig′) exceeds the amount of the Purine Derivative of Formula (Ig″).

In another embodiment, the Purine Derivatives of Formula (Ig) exist as amixture of a Purine Derivative of Formula (Ig′) and a Purine Derivativeof Formula (Ig″) wherein the amount of the Purine Derivative of Formula(Ig″) exceeds the amount of the Purine Derivative of Formula (Ig′).

In another embodiment, the Purine Derivatives of Formula (Ig) exist as aracemic mixture of a Purine Derivative of Formula (Ig′) and a PurineDerivative of Formula (Ig″).

In another embodiment, the Purine Derivatives of Formula (Ig) can existin the form of a single enantiomer, for example, that depicted by eitherformula (Igg′) or (Igg″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ig).

A Purine Derivative of Formula (Igg′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Igg″) when group A of thePurine Derivative of Formula (Igg′) is the same as group A of the PurineDerivative of Formula (Igg″) and when group D of the Purine Derivativeof Formula (Igg′) is the same as group D of the Purine Derivative ofFormula (Igg″).

A Purine Derivative of Formula (Igg″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Igg′) when group A of thePurine Derivative of Formula (Igg″) is the same as group A of the PurineDerivative of Formula (Igg′) and when group D of the Purine Derivativeof Formula (Igg″) is the same as group D of the Purine Derivative ofFormula (Igg′).

In one embodiment, the Purine Derivatives of Formula (Ig) have theformula (Igg′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ig), and wherein the PurineDerivatives of Formula (Igg′) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (Ig) have theformula (Igg″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ig), and wherein the PurineDerivatives of Formula (Igg″) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (Ig) exist as amixture of a Purine Derivative of Formula (Igg′) and a Purine Derivativeof Formula (Igg″) wherein the amount of the Purine Derivative of Formula(Igg′) exceeds the amount of the Purine Derivative of Formula (Igg″).

In a further embodiment, the Purine Derivatives of Formula (Ig) exist asa mixture of a Purine Derivative of Formula (Igg′) and a PurineDerivative of Formula (Igg″) wherein the amount of the Purine Derivativeof Formula (Igg″) exceeds the amount of the Purine Derivative of Formula(Igg′).

In another embodiment, the Purine Derivatives of Formula (Ig) exist as aracemic mixture of a Purine Derivative of Formula (Igg′) and a PurineDerivative of Formula (Igg″).

A Purine Derivative of Formula (Igg′) is the corresponding other anomerof a Purine Derivative of Formula (Ig′) when group A of the PurineDerivative of Formula (Igg′) is the same as group A of the PurineDerivative of Formula (Ig′) and when group D of the Purine Derivative ofFormula (Igg′) is the same as group D of the Purine Derivative ofFormula (Ig′).

A Purine Derivative of Formula (Ig′) is the corresponding other anomerof a Purine Derivative of Formula (Igg′) when group A of the PurineDerivative of Formula (Ig′) is the same as group A of the PurineDerivative of Formula (Igg′) and when group D of the Purine Derivativeof Formula (Ig′) is the same as group D of the Purine Derivative ofFormula (Igg′).

A Purine Derivative of Formula (Igg″) is the corresponding other anomerof a Purine Derivative of Formula (Ig″) when group A of the PurineDerivative of Formula (Igg″) is the same as group A of the PurineDerivative of Formula (Ig″) and when group D of the Purine Derivative ofFormula (Igg″) is the same as group D of the Purine Derivative ofFormula (Ig″).

A Purine Derivative of Formula (Ig″) is the corresponding other anomerof a Purine Derivative of Formula (Igg″) when group A of the PurineDerivative of Formula (Ig″) is the same as group A of the PurineDerivative of Formula (Igg″) and when group D of the Purine Derivativeof Formula (Ig″) is the same as group D of the Purine Derivative ofFormula (Igg″).

In one embodiment, the Purine Derivatives of Formula (Ig) have theformula (Igg′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ig), and wherein the PurineDerivatives of Formula (Igg′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (Ig) have theformula (Igg″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ig), and wherein the PurineDerivatives of Formula (Igg″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (Ig) have theformula (Ig′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ig), and wherein the PurineDerivatives of Formula (Ig′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (Ig) have theformula (Ig″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ig), and wherein the PurineDerivatives of Formula (Ig″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (Ig) exist as amixture of a Purine Derivative of Formula (Ig′) and a Purine Derivativeof Formula (Igg′) wherein the amount of the Purine Derivative of Formula(Ig′) exceeds the amount of the Purine Derivative of Formula (Igg′).

In another embodiment, the Purine Derivatives of Formula (Ig) exist as amixture of a Purine Derivative of Formula (Ig′) and a Purine Derivativeof Formula (Igg′) wherein the amount of the Purine Derivative of Formula(Igg′) exceeds the amount of the Purine Derivative of Formula (Ig′).

In another embodiment, the Purine Derivatives of Formula (Ig) exist as aequal mixture of a Purine Derivative of Formula (Ig′) and a PurineDerivative of Formula (Igg′).

In one embodiment, the Purine Derivatives of Formula (Ig) exist as amixture of a Purine Derivative of Formula (Ig″) and a Purine Derivativeof Formula (Igg″) wherein the amount of the Purine Derivative of Formula(Ig″) exceeds the amount of the Purine Derivative of Formula (Igg″).

In another embodiment, the Purine Derivatives of Formula (Ig) exist as amixture of a Purine Derivative of Formula (Ig″) and a Purine Derivativeof Formula (Igg″) wherein the amount of the Purine Derivative of Formula(Igg″) exceeds the amount of the Purine Derivative of Formula (Igg′).

In another embodiment, the Purine Derivatives of Formula (Ig) exist as aequal mixture of a Purine Derivative of Formula (Ig″) and a PurineDerivative of Formula (Igg″).

Illustrative Purine Derivatives of Formula (Ig) include the compoundslisted below:

and pharmaceutically acceptable salts thereof.

5.2.8 The Purine Derivatives of Formula (Ih)

As stated above, the present invention encompasses Purine Derivativeshaving the Formula (Ih):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ih), and A and B are trans with respect to each other; B and Care cis with respect to each other; and C and D are cis or trans withrespect to each other.

In one embodiment, R¹ is cyclopent-1-ol-2-yl.

In another embodiment R¹ is cyclopent-1-ol-3-yl.

In one embodiment, C and D are cis with respect to each other.

In another embodiment, C and D are trans with respect to each other.

The present invention also provides compositions comprising an effectiveamount of a Purine Derivative of Formula (Ih) and a physiologicallyacceptable carrier or vehicle.

The invention further provides Purine Derivatives of Formula (Ih) thatare in isolated and purified form.

The invention still further provides methods for treating or preventinga Condition, comprising administering an effective amount of a PurineDerivative of Formula (Ih) to an animal in need thereof.

The invention further provides methods for reducing an animal's rate ofmetabolism, comprising administering an effective amount of a PurineDerivative of Formula (Ih) to an animal in need thereof.

The invention further provides methods protecting an animal's heartagainst myocardial damage during cardioplegia, comprising administeringan effective amount of a Purine Derivative of Formula (Ih) to an animalin need thereof.

The Purine Derivatives of Formula (Ih) can exist in the form of a singleenantiomer, for example, that depicted by either the Formula (Ih′) orFormula (Ih″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ih).

A Purine Derivative of Formula (Ih′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Ih″) when group A of thePurine Derivative of Formula (Ih′) is the same as group A of the PurineDerivative of Formula (Ih″) and when group D of the Purine Derivative ofFormula (Ih′) is the same as group D of the Purine Derivative of Formula(Ib″).

A Purine Derivative of Formula (Ih″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Ih′) when group A of thePurine Derivatives of Formula (Ib″) is the same as group A of the PurineDerivative of Formula (Ih′) and when group D of the Purine Derivative ofFormula (Ih″) is the same as group D of the Purine Derivative of Formula(Ih′).

In one embodiment, the Purine Derivatives of Formula (Ih) have theformula (Ih′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ih), and wherein the PurineDerivatives of Formula (Ih′) are substantially free of theircorresponding enantiomer, represented by Formula (Ih″).

In another embodiment, the Purine Derivatives of Formula (Ih) have theformula (Ih″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ih), and wherein the PurineDerivatives of Formula (Ih″) are substantially free of theircorresponding enantiomer, represented by Formula (Ih′).

In one embodiment, the Purine Derivatives of Formula (Ih) exist as amixture of a Purine Derivative of Formula (Ih′) and a Purine Derivativeof Formula (Ih″) wherein the amount of the Purine Derivative of Formula(Ih′) exceeds the amount of the Purine Derivative of Formula (Ih″).

In another embodiment, the Purine Derivatives of Formula (Ih) exist as amixture of a Purine Derivative of Formula (Ih′) and a Purine Derivativeof Formula (Ih″) wherein the amount of the Purine Derivative of Formula(Ih″) exceeds the amount of the Purine Derivative of Formula (Ih′).

In another embodiment, the Purine Derivatives of Formula (Ih) exist as aracemic mixture of a Purine Derivative of Formula (Ih′) and a PurineDerivative of Formula (Ih″).

In another embodiment, the Purine Derivatives of Formula (Ih) can existin the form of a single enantiomer, for example, that depicted by eitherformula (Ihh′) or (Ihh″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (Ih).

A Purine Derivative of Formula (Ihh′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Ihh″) when group A of thePurine Derivative of Formula (Ihh′) is the same as group A of the PurineDerivative of Formula (Ihh″) and when group D of the Purine Derivativeof Formula (Ihh′) is the same as group D of the Purine Derivative ofFormula (Ihh″).

A Purine Derivative of Formula (Ihh″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Ihh′) when group A of thePurine Derivative of Formula (Ihh″) is the same as group A of the PurineDerivative of Formula (Ihh′) and when group D of the Purine Derivativeof Formula (Ihh″) is the same as group D of the Purine Derivative ofFormula (Ihh′).

In one embodiment, the Purine Derivatives of Formula (Ih) have theformula (Ihh′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ih), and wherein the PurineDerivatives of Formula (Ihh′) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (Ih) have theformula (Ihh″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ih), and wherein the PurineDerivatives of Formula (Ihh″) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (Ih) exist as amixture of a Purine Derivative of Formula (Ihh′) and a Purine Derivativeof Formula (Ihh″) wherein the amount of the Purine Derivative of Formula(Ihh′) exceeds the amount of the Purine Derivative of Formula (Ihh″).

In a further embodiment, the Purine Derivatives of Formula (Ih) exist asa mixture of a Purine Derivative of Formula (Ihh′) and a PurineDerivative of Formula (Ihh″) wherein the amount of the Purine Derivativeof Formula (Ihh″) exceeds the amount of the Purine Derivative of Formula(Ihh′).

In another embodiment, the Purine Derivatives of Formula (Ih) exist as aracemic mixture of a Purine Derivative of Formula (Ihh′) and a PurineDerivative of Formula (Ihh″).

A Purine Derivative of Formula (Ihh′) is the corresponding other anomerof a Purine Derivative of Formula (Ih′) when group A of the PurineDerivative of Formula (Ihh′) is the same as group A of the PurineDerivative of Formula (Ih′) and when group D of the Purine Derivative ofFormula (Ihh′) is the same as group D of the Purine Derivative ofFormula (Ih′).

A Purine Derivative of Formula (Ih′) is the corresponding other anomerof a Purine Derivative of Formula (Ihh′) when group A of the PurineDerivative of Formula (Ih′) is the same as group A of the PurineDerivative of Formula (Ihh′) and when group D of the Purine Derivativeof Formula (Ih′) is the same as group D of the Purine Derivative ofFormula (Ihh′).

A Purine Derivative of Formula (Ihh″) is the corresponding other anomerof a Purine Derivative of Formula (Ih″) when group A of the PurineDerivative of Formula (Ihh″) is the same as group A of the PurineDerivative of Formula (Ih″) and when group D of the Purine Derivative ofFormula (Ihh″) is the same as group D of the Purine Derivative ofFormula (Ib″).

A Purine Derivative of Formula (Ih″) is the corresponding other anomerof a Purine Derivative of Formula (Ihh″) when group A of the PurineDerivative of Formula (Ih″) is the same as group A of the PurineDerivative of Formula (Ihh″) and when group D of the Purine Derivativeof Formula (Ih″) is the same as group D of the Purine Derivative ofFormula (Ihh″).

In one embodiment, the Purine Derivatives of Formula (Ih) have theformula (Ihh′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ih), and wherein the PurineDerivatives of Formula (Ihh′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (Ih) have theformula (Ihh″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ih), and wherein the PurineDerivatives of Formula (Ihh″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (Ih) have theformula (Ih′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ih), and wherein the PurineDerivatives of Formula (Ih′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (Ih) have theformula (Ih″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (Ih), and wherein the PurineDerivatives of Formula (Ih″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (Ih) exist as amixture of a Purine Derivative of Formula (Ih′) and a Purine Derivativeof Formula (Ihh′) wherein the amount of the Purine Derivative of Formula(Ih′) exceeds the amount of the Purine Derivative of Formula (Ihh′).

In another embodiment, the Purine Derivatives of Formula (Ih) exist as amixture of a Purine Derivative of Formula (Ih′) and a Purine Derivativeof Formula (Ihh′) wherein the amount of the Purine Derivative of Formula(Ihh′) exceeds the amount of the Purine Derivative of Formula (Ih′).

In another embodiment, the Purine Derivatives of Formula (Ih) exist as aequal mixture of a Purine Derivative of Formula (Ih′) and a PurineDerivative of Formula (Ihh′).

In one embodiment, the Purine Derivatives of Formula (Ih) exist as amixture of a Purine Derivative of Formula (Ih″) and a Purine Derivativeof Formula (Ihh″) wherein the amount of the Purine Derivative of Formula(Ih″) exceeds the amount of the Purine Derivative of Formula (Ihh″).

In another embodiment, the Purine Derivatives of Formula (Ih) exist as amixture of a Purine Derivative of Formula (Ih″) and a Purine Derivativeof Formula (Ihh″) wherein the amount of the Purine Derivative of Formula(Ihh″) exceeds the amount of the Purine Derivative of Formula (Ih″).

In another embodiment, the Purine Derivatives of Formula (Ih) exist as aequal mixture of a Purine Derivative of Formula (Ih″) and a PurineDerivative of Formula (Ihh″).

Illustrative Purine Derivatives of Formula (Ih) include the compoundslisted below:

and pharmaceutically acceptable salts thereof.

5.2.9 The Purine Derivatives of Formula (II)

As stated above, the present invention encompasses Purine Derivativeshaving the Formula (II):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (II), and A and B are trans with respect to each other; B and Care cis with respect to each other; and C and D are cis or trans withrespect to each other.

In one embodiment, R¹ is —H.

In another embodiment, R¹ is —C₁-C₁₀ alkyl.

In still another embodiment, R¹ is —(CH₂)_(m)—(C₈-C₁₂ bicycliccycloalkyl) or —(CH₂)_(m)—(C₈-C₁₂ bicyclic cycloalkenyl).

In another embodiment, R² is —OR⁴ or —SR.

In another embodiment, R² is —NHNHC(O)R³, —NHNHC(O)OR⁷ or —NHNHC(O)NHR³.

In yet another embodiment, R² is —NH—N═C(R⁵)R⁶.

In a specific embodiment, R² is —NH—N═CH-cyclopropyl.

In one embodiment, C and D are cis with respect to each other.

In another embodiment, C and D are trans with respect to each other.

The present invention also provides compositions comprising an effectiveamount of a Purine Derivative of Formula (II) and a physiologicallyacceptable carrier or vehicle.

The invention further provides Purine Derivatives of Formula (II) thatare in isolated and purified form.

The invention still further provides methods for treating or preventinga Condition, comprising administering an effective amount of a PurineDerivative of Formula (II) to an animal in need thereof.

The invention further provides methods for reducing an animal's rate ofmetabolism, comprising administering an effective amount of a PurineDerivative of Formula (II) to an animal in need thereof.

The invention further provides methods protecting an animal's heartagainst myocardial damage during cardioplegia, comprising administeringan effective amount of a Purine Derivative of Formula (II) to an animalin need thereof.

The Purine Derivatives of Formula (II) can exist in the form of a singleenantiomer, for example, that depicted by either the Formula (II′) orFormula (II″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (II).

A Purine Derivative of Formula (II) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (II″) when group A of thePurine Derivative of Formula (II′) is the same as group A of the PurineDerivative of Formula (II″) and when group D of the Purine Derivative ofFormula (II′) is the same as group D of the Purine Derivative of Formula(II″).

A Purine Derivative of Formula (II″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (II′) when group A of thePurine Derivatives of Formula (II″) is the same as group A of the PurineDerivative of Formula (IT) and when group D of the Purine Derivative ofFormula (II″) is the same as group D of the Purine Derivative of Formula(II′).

In one embodiment, the Purine Derivatives of Formula (II) have theformula (II′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (II), and wherein the PurineDerivatives of Formula (II′) are substantially free of theircorresponding enantiomer, represented by Formula (II″).

In another embodiment, the Purine Derivatives of Formula (II) have theformula (II″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (II), and wherein the PurineDerivatives of Formula (II″) are substantially free of theircorresponding enantiomer, represented by Formula (II′).

In one embodiment, the Purine Derivatives of Formula (II) exist as amixture of a Purine Derivative of Formula (II′) and a Purine Derivativeof Formula (II″) wherein the amount of the Purine Derivative of Formula(II′) exceeds the amount of the Purine Derivative of Formula (II″).

In another embodiment, the Purine Derivatives of Formula (II) exist as amixture of a Purine Derivative of Formula (II′) and a Purine Derivativeof Formula (II″) wherein the amount of the Purine Derivative of Formula(II″) exceeds the amount of the Purine Derivative of Formula (II′).

In another embodiment, the Purine Derivatives of Formula (II) exist as aracemic mixture of a Purine Derivative of Formula (II′) and a PurineDerivative of Formula (II″).

In another embodiment, the Purine Derivatives of Formula (II) can existin the form of a single enantiomer, for example, that depicted by eitherformula (IIa′) or (IIa″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (II).

A Purine Derivative of Formula (IIa′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (IIa″) when group A of thePurine Derivative of Formula (IIa′) is the same as group A of the PurineDerivative of Formula (IIa″) and when group D of the Purine Derivativeof Formula (IIa′) is the same as group D of the Purine Derivative ofFormula (IIa″).

A Purine Derivative of Formula (IIa″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (IIa′) when group A of thePurine Derivative of Formula (IIa″) is the same as group A of the PurineDerivative of Formula (IIa′) and when group D of the Purine Derivativeof Formula (IIa″) is the same as group D of the Purine Derivative ofFormula (IIa′).

In one embodiment, the Purine Derivatives of Formula (II) have theformula (IIa′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (II), and wherein the PurineDerivatives of Formula (IIa′) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (II) have theformula (IIa″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (II), and wherein the PurineDerivatives of Formula (IIa″) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (II) exist as amixture of a Purine Derivative of Formula (IIa′) and a Purine Derivativeof Formula (IIa″) wherein the amount of the Purine Derivative of Formula(IIa′) exceeds the amount of the Purine Derivative of Formula (IIa″).

In a further embodiment, the Purine Derivatives of Formula (II) exist asa mixture of a Purine Derivative of Formula (IIa′) and a PurineDerivative of Formula (IIa″) wherein the amount of the Purine Derivativeof Formula (IIa″) exceeds the amount of the Purine Derivative of Formula(Ia′).

In another embodiment, the Purine Derivatives of Formula (II) exist as aracemic mixture of a Purine Derivative of Formula (IIa′) and a PurineDerivative of Formula (IIa″).

A Purine Derivative of Formula (IIa′) is the corresponding other anomerof a Purine Derivative of Formula (II′) when group A of the PurineDerivative of Formula (II′) is the same as group A of the PurineDerivative of Formula (II′) and when group D of the Purine Derivative ofFormula (IIa′) is the same as group D of the Purine Derivative ofFormula (II′).

A Purine Derivative of Formula (II′) is the corresponding other anomerof a Purine Derivative of Formula (IIa′) when group A of the PurineDerivative of Formula (II′) is the same as group A of the PurineDerivative of Formula (IIa′) and when group D of the Purine Derivativeof Formula (II′) is the same as group D of the Purine Derivative ofFormula (IIa′).

A Purine Derivative of Formula (IIa″) is the corresponding other anomerof a Purine Derivative of Formula (II″) when group A of the PurineDerivative of Formula (IIa″) is the same as group A of the PurineDerivative of Formula (II″) and when group D of the Purine Derivative ofFormula (IIa″) is the same as group D of the Purine Derivative ofFormula (II″).

A Purine Derivative of Formula (II″) is the corresponding other anomerof a Purine Derivative of Formula (IIa″) when group A of the PurineDerivative of Formula (II″) is the same as group A of the PurineDerivative of Formula (IIa″) and when group D of the Purine Derivativeof Formula (II″) is the same as group D of the Purine Derivative ofFormula (IIa″).

In one embodiment, the Purine Derivatives of Formula (II) have theformula (IIa′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (II), and wherein the PurineDerivatives of Formula (IIa′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (II) have theformula (IIa″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (II), and wherein the PurineDerivatives of Formula (IIa″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (II) have theformula (II′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (II), and wherein the PurineDerivatives of Formula (II′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (II) have theformula (II″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (II), and wherein the PurineDerivatives of Formula (II″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (II) exist as amixture of a Purine Derivative of Formula (II′) and a Purine Derivativeof Formula (IIa′) wherein the amount of the Purine Derivative of Formula(II′) exceeds the amount of the Purine Derivative of Formula (IIa′)

In another embodiment, the Purine Derivatives of Formula (II) exist as amixture of a Purine Derivative of Formula (II′) and a Purine Derivativeof Formula (IIa′) wherein the amount of the Purine Derivative of Formula(IIa′) exceeds the amount of the Purine Derivative of Formula (II′).

In another embodiment, the Purine Derivatives of Formula (IIa) exist asa equal mixture of a Purine Derivative of Formula (II′) and a PurineDerivative of Formula (IIa′).

In one embodiment, the Purine Derivatives of Formula (IIa) exist as amixture of a Purine Derivative of Formula (II″) and a Purine Derivativeof Formula (IIa″) wherein the amount of the Purine Derivative of Formula(II″) exceeds the amount of the Purine Derivative of Formula (IIa″).

In another embodiment, the Purine Derivatives of Formula (IIa) exist asa mixture of a Purine Derivative of Formula (II″) and a PurineDerivative of Formula (IIa″) wherein the amount of the Purine Derivativeof Formula (IIa″) exceeds the amount of the Purine Derivative of Formula(II″).

In another embodiment, the Purine Derivatives of Formula (IIa) exist asa equal mixture of a Purine Derivative of Formula (II″) and a PurineDerivative of Formula (IIa″).

A first subclass of the Purine Derivatives of Formula (II) is thatwherein one occurrence of R¹ is —H.

A second subclass of the Purine Derivatives of Formula (II) is thatwherein both R¹ groups together with the carbon atom to which they areattached, join to form a —C₃-C₈ monocyclic cycloalkyl.

A third subclass of the Purine Derivatives of Formula (II) is thatwherein R² is —NH—N═C(R⁵)R⁶

5.2.10 The Purine Derivatives of Formula (III)

As stated above, the present invention encompasses Purine Derivativeshaving the Formula (III):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (m), and A and B are trans with respect to each other; B and Care cis with respect to each other; and C and D are cis or trans withrespect to each other.

In one embodiment, R¹ is —H.

In another embodiment, R¹ is —C₁-C₁₀ alkyl.

In another embodiment, R¹ is —(CH₂)_(m)-(3- to 7-membered monocyclicheterocycle) or —(CH₂)_(m)-(8- to 12-membered bicyclic heterocycle).

In still another embodiment, R¹ is —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkyl) or —(CH₂)_(m)—(C₃-C₈ monocyclic cycloalkenyl),

In a further embodiment, R¹ is —(CH₂)_(m)—(C₈-C₁₂ bicyclic cycloalkyl)or —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl).

In another embodiment, R¹ is —(CH₂)_(m)-aryl.

In still another embodiment, two R¹ groups, together with the carbonatom to which they are attached, form a —C₃-C₈ monocyclic cycloalkyl, a—C₃-C₈ monocyclic cycloalkenyl, a —C₈-C₁₂ bicyclic cycloalkyl, or a—C₈-C₁₂ bicyclic cycloalkenyl.

In a specific embodiment, R¹ is cyclopentyl.

In one embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In still another embodiment, m is 3.

In one embodiment, R² is -halo.

In a specific embodiment, R² is —Cl.

In one embodiment, R² is —H.

In another embodiment, R² is —CN.

In another embodiment, R² is —N(R⁴)₂, —OR⁴ or —SR⁴.

In a further embodiment, R² is —NHC(O)R⁴, —NHC(O)OR⁴ or —NHC(O)NHR⁴.

In another embodiment, R² is —NHNHC(O)R⁴, —NHNHC(O)OR⁴ or —NHNHC(O)NHR⁴.In yet another embodiment, R² is —NH—N═C(R⁶)R⁷.

In a specific embodiment, R² is —NH—N═CH-cyclopropyl.

In one embodiment, R³ is —ONO₂ or —ONO.

In another embodiment, R³ is —OSO₃H, —OSO₂NH₂, —OSO₂NH(C₁-C₁₀ alkyl),—OSO₂N(C₁-C₁₀ alkyl)₂ or —OSO₂NH-aryl.

In another embodiment, R³ is —N(R⁵)₂.

In one embodiment, C and D are cis with respect to each other.

In another embodiment, C and D are trans with respect to each other.

The present invention also provides compositions comprising an effectiveamount of a Purine Derivative of Formula (III) and a physiologicallyacceptable carrier or vehicle.

The invention further provides Purine Derivatives of Formula (III) thatare in isolated and purified form.

The invention still further provides methods for treating or preventinga Condition, comprising administering an effective amount of a PurineDerivative of Formula (III) to an animal in need thereof.

The invention further provides methods for reducing an animal's rate ofmetabolism, comprising administering an effective amount of a PurineDerivative of Formula (III) to an animal in need thereof.

The invention further provides methods protecting an animal's heartagainst myocardial damage during cardioplegia, comprising administeringan effective amount of a Purine Derivative of Formula (III) to an animalin need thereof.

The Purine Derivatives of Formula (III) can exist in the form of asingle enantiomer, for example, that depicted by either the Formula(III′) or Formula (III″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (III).

A Purine Derivative of Formula (III′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (III″) when group A of thePurine Derivative of Formula (III″) is the same as group A of the PurineDerivative of Formula (III″) and when group D of the Purine Derivativeof Formula (III″) is the same as group D of the Purine Derivative ofFormula (III″).

A Purine Derivative of Formula (III″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (III′) when group A of thePurine Derivatives of Formula (III″) is the same as group A of thePurine Derivative of Formula (III′) and when group D of the PurineDerivative of Formula (III″) is the same as group D of the PurineDerivative of Formula (III′).

In one embodiment, the Purine Derivatives of Formula (III) have theformula (III′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (III), and wherein the PurineDerivatives of Formula (III′) are substantially free of theircorresponding enantiomer, represented by Formula (III″).

In another embodiment, the Purine Derivatives of Formula (III) have theformula (III″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (III), and wherein the PurineDerivatives of Formula (III″) are substantially free of theircorresponding enantiomer, represented by Formula (III″).

In one embodiment, the Purine Derivatives of Formula (III) exist as amixture of a Purine Derivative of Formula (III′) and a Purine Derivativeof Formula (III″) wherein the amount of the Purine Derivative of Formula(III′) exceeds the amount of the Purine Derivative of Formula (III″).

In another embodiment, the Purine Derivatives of Formula (III) exist asa mixture of a Purine Derivative of Formula (III′) and a PurineDerivative of Formula (III″) wherein the amount of the Purine Derivativeof Formula (III″) exceeds the amount of the Purine Derivative of Formula(III′).

In another embodiment, the Purine Derivatives of Formula (III) exist asa racemic mixture of a Purine Derivative of Formula (III′) and a PurineDerivative of Formula (III″).

In another embodiment, the Purine Derivatives of Formula (III) can existin the form of a single enantiomer, for example, that depicted by eitherformula (IIIa′) or (IIIa″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (III).

A Purine Derivative of Formula (IIIa′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (IIIa″) when group A of thePurine Derivative of Formula (III′) is the same as group A of the PurineDerivative of Formula (III″) and when group D of the Purine Derivativeof Formula (III′) is the same as group D of the Purine Derivative ofFormula (III″).

A Purine Derivative of Formula (III″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (III′) when group A of thePurine Derivative of Formula (III″) is the same as group A of the PurineDerivative of Formula (III′) and when group D of the Purine Derivativeof Formula (III″) is the same as group D of the Purine Derivative ofFormula (III′).

In one embodiment, the Purine Derivatives of Formula (III) have theformula (IIIa′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (III), and wherein the PurineDerivatives of Formula (IIIa′) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (III) have theformula (III″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (III), and wherein the PurineDerivatives of Formula (III″) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (III) exist asa mixture of a Purine Derivative of Formula (IIIa′) and a PurineDerivative of Formula (IIIa″) wherein the amount of the PurineDerivative of Formula (IIIa′) exceeds the amount of the PurineDerivative of Formula (IIIa″).

In a further embodiment, the Purine Derivatives of Formula (III) existas a mixture of a Purine Derivative of Formula (IIIa′) and a PurineDerivative of Formula (IIIa″) wherein the amount of the PurineDerivative of Formula (IIIa″) exceeds the amount of the PurineDerivative of Formula (IIIa′).

In another embodiment, the Purine Derivatives of Formula (III) exist asa racemic mixture of a Purine Derivative of Formula (IIIa′) and a PurineDerivative of Formula (IIIa″).

A Purine Derivative of Formula (III) is the corresponding other anomerof a Purine Derivative of Formula (III′) when group A of the PurineDerivative of Formula (III″) is the same as group A of the PurineDerivative of Formula (III′) and when group D of the Purine Derivativeof Formula (III′) is the same as group D of the Purine Derivative ofFormula (III′).

A Purine Derivative of Formula (III′) is the corresponding other anomerof a Purine Derivative of Formula (III′) when group A of the PurineDerivative of Formula (III′) is the same as group A of the PurineDerivative of Formula (IIIa′) and when group D of the Purine Derivativeof Formula (III′) is the same as group D of the Purine Derivative ofFormula (IIa′).

A Purine Derivative of Formula (IIIa″) is the corresponding other anomerof a Purine Derivative of Formula (III″) when group A of the PurineDerivative of Formula (IIIa″) is the same as group A of the PurineDerivative of Formula (III″) and when group D of the Purine Derivativeof Formula (IIIa″) is the same as group D of the Purine Derivative ofFormula (III″).

A Purine Derivative of Formula (III″) is the corresponding other anomerof a Purine Derivative of Formula (IIIa″) when group A of the PurineDerivative of Formula (III″) is the same as group A of the PurineDerivative of Formula (IIIa″) and when group D of the Purine Derivativeof Formula (III″) is the same as group D of the Purine Derivative ofFormula (IIIa″).

In one embodiment, the Purine Derivatives of Formula (III) have theformula (IIIa′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (III), and wherein the PurineDerivatives of Formula (IIIa′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (III) have theformula (IIIa″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (III), and wherein the PurineDerivatives of Formula (IIIa″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (III) have theformula (III′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (III), and wherein the PurineDerivatives of Formula (III′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (III) have theformula (III″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (III), and wherein the PurineDerivatives of Formula (III″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (III) exist as amixture of a Purine Derivative of Formula (III′) and a Purine Derivativeof Formula (IIIa′) wherein the amount of the Purine Derivative ofFormula (III′) exceeds the amount of the Purine Derivative of Formula(IIIa′)

In another embodiment, the Purine Derivatives of Formula (III) exist asa mixture of a Purine Derivative of Formula (III′) and a PurineDerivative of Formula (IIIa′) wherein the amount of the PurineDerivative of Formula (IIIa′) exceeds the amount of the PurineDerivative of Formula (III′).

In another embodiment, the Purine Derivatives of Formula (IIIa) exist asa equal mixture of a Purine Derivative of Formula (III′) and a PurineDerivative of Formula (IIIa′).

In one embodiment, the Purine Derivatives of Formula (IIIa) exist as amixture of a Purine Derivative of Formula (III″) and a Purine Derivativeof Formula (IIIa″) wherein the amount of the Purine Derivative ofFormula (III″) exceeds the amount of the Purine Derivative of Formula(III″).

In another embodiment, the Purine Derivatives of Formula (IIIa) exist asa mixture of a Purine Derivative of Formula (III″) and a PurineDerivative of Formula (IIIa″) wherein the amount of the PurineDerivative of Formula (IIIa″) exceeds the amount of the PurineDerivative of Formula (III″).

In another embodiment, the Purine Derivatives of Formula (IIIa) exist asa equal mixture of a Purine Derivative of Formula (III″) and a PurineDerivative of Formula (III″).

A first subclass of the Purine Derivatives of Formula (III) is thatwherein one occurrence of R¹ is —H.

A second subclass of the Purine Derivatives of Formula (III) is thatwherein one occurrence of R¹ is —H and the other occurrence of R¹ is—C₃-C₈ monocyclic cycloalkyl.

A third subclass of the Purine Derivatives of Formula (IE) is thatwherein R² is —NH—N═C(R⁵)R⁶.

A fourth subclass of the Purine Derivatives of Formula (III) is thatwherein R³ is —ONO₂.

5.2.11 The Purine Derivatives of Formula (IV)

As stated above, the present invention encompasses Purine Derivativeshaving the Formula (IV):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (IV), and A and B are trans with respect to each other; B and Care cis with respect to each other; and C and D are cis or trans withrespect to each other.

In one embodiment, R¹ is —C₃-C₈ monocyclic cycloalkyl.

In another embodiment, R¹ is —C₃-C₈ monocyclic cycloalkenyl.

In a specific embodiment, R¹ is cyclopentyl.

In one embodiment, R² is —H.

In another embodiment, R² is -halo.

In a specific embodiment, R² is —Cl.

In another embodiment, R² is —CN.

In another embodiment, R² is —N(R³)₂, —OR³ or —SR³.

In another embodiment, R² is —NHNHC(O)R³, —NHNHC(O)OR³ or —NHNHC(O)NHR³.In yet another embodiment, R² is —NH—N═C(R⁴)R⁵.

In a specific embodiment, R² is —NH—N═CH-cyclopropyl.

In one embodiment, C and D are cis with respect to each other.

In another embodiment, C and D are trans with respect to each other.

The present invention also provides compositions comprising an effectiveamount of a Purine Derivative of Formula (IV) and a physiologicallyacceptable carrier or vehicle.

The invention further provides Purine Derivatives of Formula (IV) thatare in isolated and purified form.

The invention still further provides methods for treating or preventinga Condition, comprising administering an effective amount of a PurineDerivative of Formula (IV) to an animal in need thereof.

The invention further provides methods for reducing an animal's rate ofmetabolism, comprising administering an effective amount of a PurineDerivative of Formula (IV) to an animal in need thereof.

The invention further provides methods protecting an animal's heartagainst myocardial damage during cardioplegia, comprising administeringan effective amount of a Purine Derivative of Formula (IV) to an animalin need thereof.

The Purine Derivatives of Formula (IV) can exist in the form of a singleenantiomer, for example, that depicted by either the Formula (IV′) orFormula (IV″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (IV).

A Purine Derivative of Formula (IV′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (IV″) when group A of thePurine Derivative of Formula (IV′) is the same as group A of the PurineDerivative of Formula (IV″) and when group D of the Purine Derivative ofFormula (IV′) is the same as group D of the Purine Derivative of Formula(IV″).

A Purine Derivative of Formula (IV″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (IV′) when group A of thePurine Derivatives of Formula (IV″) is the same as group A of the PurineDerivative of Formula (IV′) and when group D of the Purine Derivative ofFormula (IV″) is the same as group D of the Purine Derivative of Formula(IV′).

In one embodiment, the Purine Derivatives of Formula (IV) have theformula (IV′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (IV), and wherein the PurineDerivatives of Formula (IV′) are substantially free of theircorresponding enantiomer, represented by Formula (IV″).

In another embodiment, the Purine Derivatives of Formula (IV) have theformula (IV″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (IV), and wherein the PurineDerivatives of Formula (IV″) are substantially free of theircorresponding enantiomer, represented by Formula (IV′).

In one embodiment, the Purine Derivatives of Formula (IV) exist as amixture of a Purine Derivative of Formula (IV′) and a Purine Derivativeof Formula (IV″) wherein the amount of the Purine Derivative of Formula(IV′) exceeds the amount of the Purine Derivative of Formula (IV″).

In another embodiment, the Purine Derivatives of Formula (IV) exist as amixture of a Purine Derivative of Formula (IV′) and a Purine Derivativeof Formula (IV″) wherein the amount of the Purine Derivative of Formula(IV″) exceeds the amount of the Purine Derivative of Formula (IV′).

In another embodiment, the Purine Derivatives of Formula (IV) exist as aracemic mixture of a Purine Derivative of Formula (IV′) and a PurineDerivative of Formula (IV″)

In another embodiment, the Purine Derivatives of Formula (IV) can existin the form of a single enantiomer, for example, that depicted by eitherformula (IVa′) or (IVa″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (IV).

A Purine Derivative of Formula (IVa′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (IVa″) when group A of thePurine Derivative of Formula (IVa′) is the same as group A of the PurineDerivative of Formula (IVa″) and when group D of the Purine Derivativeof Formula (IVa′) is the same as group D of the Purine Derivative ofFormula (IVa″).

A Purine Derivative of Formula (IVa″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (IVa′) when group A of thePurine Derivative of Formula (IVa″) is the same as group A of the PurineDerivative of Formula (IVa′) and when group D of the Purine Derivativeof Formula (IVa″) is the same as group D of the Purine Derivative ofFormula (IVa′).

In one embodiment, the Purine Derivatives of Formula (IV) have theformula (IVa′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (IV), and wherein the PurineDerivatives of Formula (IVa′) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (IV) have theformula (IVa″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (IV), and wherein the PurineDerivatives of Formula (IVa″) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (IV) exist as amixture of a Purine Derivative of Formula (IVa′) and a Purine Derivativeof Formula (IVa″) wherein the amount of the Purine Derivative of Formula(IVa′) exceeds the amount of the Purine Derivative of Formula (IVa″).

In a further embodiment, the Purine Derivatives of Formula (IV) exist asa mixture of a Purine Derivative of Formula (IVa′) and a PurineDerivative of Formula (IVa″) wherein the amount of the Purine Derivativeof Formula (IVa″) exceeds the amount of the Purine Derivative of Formula(IVa′).

In another embodiment, the Purine Derivatives of Formula (IV) exist as aracemic mixture of a Purine Derivative of Formula (IVa′) and a PurineDerivative of Formula (IVa″).

A Purine Derivative of Formula (IVa′) is the corresponding other anomerof a Purine Derivative of Formula (IV′) when group A of the PurineDerivative of Formula (IVa′) is the same as group A of the PurineDerivative of Formula (IV′) and when group D of the Purine Derivative ofFormula (IVa′) is the same as group D of the Purine Derivative ofFormula (IV′).

A Purine Derivative of Formula (IV′) is the corresponding other anomerof a Purine Derivative of Formula (IVa′) when group A of the PurineDerivative of Formula (IV′) is the same as group A of the PurineDerivative of Formula (IVa′) and when group D of the Purine Derivativeof Formula (IV′) is the same as group D of the Purine Derivative ofFormula (IVa′).

A Purine Derivative of Formula (IVa″) is the corresponding other anomerof a Purine Derivative of Formula (IV″) when group A of the PurineDerivative of Formula (IVa″) is the same as group A of the PurineDerivative of Formula (IV″) and when group D of the Purine Derivative ofFormula (IVa″) is the same as group D of the Purine Derivative ofFormula (IV″).

A Purine Derivative of Formula (IV″) is the corresponding other anomerof a Purine Derivative of Formula (IVa″) when group A of the PurineDerivative of Formula (IV″) is the same as group A of the PurineDerivative of Formula (IVa″) and when group D of the Purine Derivativeof Formula (IV″) is the same as group D of the Purine Derivative ofFormula (IVa″).

In one embodiment, the Purine Derivatives of Formula (IV) have theformula (IVa′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (IV), and wherein the PurineDerivatives of Formula (IVa′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (IV) have theformula (IVa″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (IV), and wherein the PurineDerivatives of Formula (IVa″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (IV) have theformula (IV′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (IV), and wherein the PurineDerivatives of Formula (IV′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (IV) have theformula (IV″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (IV), and wherein the PurineDerivatives of Formula (IV″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (IV) exist as amixture of a Purine Derivative of Formula (IV′) and a Purine Derivativeof Formula (IVa′) wherein the amount of the Purine Derivative of Formula(IV′) exceeds the amount of the Purine Derivative of Formula (IVa′)

In another embodiment, the Purine Derivatives of Formula (IV) exist as amixture of a Purine Derivative of Formula (IV′) and a Purine Derivativeof Formula (IVa′) wherein the amount of the Purine Derivative of Formula(IVa′) exceeds the amount of the Purine Derivative of Formula (IV′).

In another embodiment, the Purine Derivatives of Formula (IVa) exist asa equal mixture of a Purine Derivative of Formula (IV′) and a PurineDerivative of Formula (IVa′).

In one embodiment, the Purine Derivatives of Formula (IVa) exist as amixture of a Purine Derivative of Formula (IV″) and a Purine Derivativeof Formula (IVa″) wherein the amount of the Purine Derivative of Formula(IV″) exceeds the amount of the Purine Derivative of Formula (IVa″).

In another embodiment, the Purine Derivatives of Formula (IVa) exist asa mixture of a Purine Derivative of Formula (IV″) and a PurineDerivative of Formula (IVa″) wherein the amount of the Purine Derivativeof Formula (IVa″) exceeds the amount of the Purine Derivative of Formula(IV″).

In another embodiment, the Purine Derivatives of Formula (IVa) exist asa equal mixture of a Purine Derivative of Formula (IV″) and a PurineDerivative of Formula (IVa″).

A first subclass of the Purine Derivatives of Formula (IV) is thatwherein R¹ is -cyclopentyl.

A second subclass of the Purine Derivatives of Formula (IV) is thatwherein R² is —H.

A third subclass of the Purine Derivatives of Formula (IV) is thatwherein R² is —Cl.

Illustrative Purine Derivatives of Formula (IV) include the compoundslisted below:

and pharmaceutically acceptable salts thereof.

5.2.12 The Purine Derivatives of Formula (V)

As stated above, the present invention encompasses Purine Derivativeshaving the Formula (V):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (V), and A and B are trans with respect to each other; B and Care cis with respect to each other; and C and D are cis or trans withrespect to each other.

In one embodiment, R¹ is —C₁-C₁₀ alkyl.

In another embodiment, R¹ is —(CH₂)_(m)-(3- to 7-membered monocyclicheterocycle) or —(CH₂)_(m)-(8- to 12-membered bicyclic heterocycle).

In another embodiment, R¹ is —(CH₂)_(m)—(C₈-C₁₂ bicyclic cycloalkyl) or—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl).

In still another embodiment, R¹ is —(CH₂)_(m)—(C₃-C₈ monocycliccycloalkyl) or —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl).

In a further embodiment, R¹ is —(CH₂)_(m)-aryl.

In one embodiment, R^(1a) is —C₃-C₈ monocyclic cycloalkyl.

In another embodiment, R^(1a) is —C₃-C₈ monocyclic cycloalkenyl.

In a specific embodiment, R^(1a) is cyclopentyl.

In another embodiment, R¹ and R^(1a) together with the carbon atom towhich they are attached form a —C₃-C₈ monocyclic cycloalkyl, a —C₃-C₈monocyclic cycloalkenyl, a —C₈-C₁₂ bicyclic cycloalkyl, or a —C₈-C₁₂bicyclic cycloalkenyl.

In one embodiment, R² is —OR⁴ or —SR⁴.

In another embodiment, R² is —NHNHC(O)R³, —NHNHC(O)OR³ or —NHNHC(O)NHR³.In yet another embodiment, R² is —NH—N═C(R⁵)R⁶.

In a specific embodiment, R² is —NH—N═CH-cyclopropyl.

In one embodiment, C and D are cis with respect to each other.

In another embodiment, C and D are trans with respect to each other.

The present invention also provides compositions comprising an effectiveamount of a Purine Derivative of Formula (V) and a physiologicallyacceptable carrier or vehicle.

The invention further provides Purine Derivatives of Formula (V) thatare in isolated and purified form.

The invention still further provides methods for treating or preventinga Condition, comprising administering an effective amount of a PurineDerivative of Formula (V) to an animal in need thereof.

The invention further provides methods for reducing an animal's rate ofmetabolism, comprising administering an effective amount of a PurineDerivative of Formula (V) to an animal in need thereof.

The invention further provides methods protecting an animal's heartagainst myocardial damage during cardioplegia, comprising administeringan effective amount of a Purine Derivative of Formula (V) to an animalin need thereof.

The Purine Derivatives of Formula (V) can exist in the form of a singleenantiomer, for example, that depicted by either the Formula (V′) orFormula (V″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (V).

A Purine Derivative of Formula (V′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (V″) when group A of thePurine Derivative of Formula (V′) is the same as group A of the PurineDerivative of Formula (V″) and when group D of the Purine Derivative ofFormula (V′) is the same as group D of the Purine Derivative of Formula(V″).

A Purine Derivative of Formula (V″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (V′) when group A of thePurine Derivatives of Formula (V″) is the same as group A of the PurineDerivative of Formula (V′) and when group D of the Purine Derivative ofFormula (V″) is the same as group D of the Purine Derivative of Formula(V′).

In one embodiment, the Purine Derivatives of Formula (V) have theformula (V′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (V), and wherein the PurineDerivatives of Formula (V′) are substantially free of theircorresponding enantiomer, represented by Formula (V″).

In another embodiment, the Purine Derivatives of Formula (V) have theformula (V″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (V), and wherein the PurineDerivatives of Formula (V″) are substantially free of theircorresponding enantiomer, represented by Formula (V′).

In one embodiment, the Purine Derivatives of Formula (V) exist as amixture of a Purine Derivative of Formula (V′) and a Purine Derivativeof Formula (V″) wherein the amount of the Purine Derivative of Formula(V′) exceeds the amount of the Purine Derivative of Formula (V″).

In another embodiment, the Purine Derivatives of Formula (V) exist as amixture of a Purine Derivative of Formula (V′) and a Purine Derivativeof Formula (V″) wherein the amount of the Purine Derivative of Formula(V″) exceeds the amount of the Purine Derivative of Formula (V′).

In another embodiment, the Purine Derivatives of Formula (V) exist as aracemic mixture of a Purine Derivative of Formula (V′) and a PurineDerivative of Formula (V″)

In another embodiment, the Purine Derivatives of Formula (V) can existin the form of a single enantiomer, for example, that depicted by eitherformula (Va′) or (Va″):

wherein A, B, C and D are defined above for the Purine Derivatives ofFormula (V).

A Purine Derivative of Formula (Va′) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Va″) when group A of thePurine Derivative of Formula (Va′) is the same as group A of the PurineDerivative of Formula (Va″) and when group D of the Purine Derivative ofFormula (Va′) is the same as group D of the Purine Derivative of Formula(Va″).

A Purine Derivative of Formula (Va″) is the corresponding oppositeenantiomer of a Purine Derivative of Formula (Va′) when group A of thePurine Derivative of Formula (Va″) is the same as group A of the PurineDerivative of Formula (Va′) and when group D of the Purine Derivative ofFormula (Va″) is the same as group D of the Purine Derivative of Formula(Va′).

In one embodiment, the Purine Derivatives of Formula (V) have theformula (Va′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (V), and wherein the PurineDerivatives of Formula (Va′) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (V) have theformula (Va″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (V), and wherein the PurineDerivatives of Formula (Va″) are substantially free of theircorresponding opposite enantiomer.

In another embodiment, the Purine Derivatives of Formula (V) exist as amixture of a Purine Derivative of Formula (Va′) and a Purine Derivativeof Formula (Va″) wherein the amount of the Purine Derivative of Formula(Va′) exceeds the amount of the Purine Derivative of Formula (Va″).

In a further embodiment, the Purine Derivatives of Formula (V) exist asa mixture of a Purine Derivative of Formula (Va′) and a PurineDerivative of Formula (Va″) wherein the amount of the Purine Derivativeof Formula (Va″) exceeds the amount of the Purine Derivative of Formula(Va′).

In another embodiment, the Purine Derivatives of Formula (V) exist as aracemic mixture of a Purine Derivative of Formula (Va′) and a PurineDerivative of Formula (Va″).

A Purine Derivative of Formula (Va′) is the corresponding other anomerof a Purine Derivative of Formula (V′) when group A of the PurineDerivative of Formula (Va′) is the same as group A of the PurineDerivative of Formula (V′) and when group D of the Purine Derivative ofFormula (Va′) is the same as group D of the Purine Derivative of Formula(V′).

A Purine Derivative of Formula (V′) is the corresponding other anomer ofa Purine Derivative of Formula (Va′) when group A of the PurineDerivative of Formula (V′) is the same as group A of the PurineDerivative of Formula (Va′) and when group D of the Purine Derivative ofFormula (V′) is the same as group D of the Purine Derivative of Formula(Va′).

A Purine Derivative of Formula (Va″) is the corresponding other anomerof a Purine Derivative of Formula (V″) when group A of the PurineDerivative of Formula (Va″) is the same as group A of the PurineDerivative of Formula (V″) and when group D of the Purine Derivative ofFormula (Va″) is the same as group D of the Purine Derivative of Formula(V″).

A Purine Derivative of Formula (V″) is the corresponding other anomer ofa Purine Derivative of Formula (Va″) when group A of the PurineDerivative of Formula (V″) is the same as group A of the PurineDerivative of Formula (Va″) and when group D of the Purine Derivative ofFormula (V″) is the same as group D of the Purine Derivative of Formula(Va″).

In one embodiment, the Purine Derivatives of Formula (V) have theformula (Va′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (V), and wherein the PurineDerivatives of Formula (Va′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (V) have theformula (Va″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (V), and wherein the PurineDerivatives of Formula (Va″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (V) have theformula (V′), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (V), and wherein the PurineDerivatives of Formula (V′) are substantially free of theircorresponding other anomer.

In another embodiment, the Purine Derivatives of Formula (V) have theformula (V″), depicted above, wherein A, B, C and D are defined abovefor the Purine Derivatives of Formula (V), and wherein the PurineDerivatives of Formula (V″) are substantially free of theircorresponding other anomer.

In one embodiment, the Purine Derivatives of Formula (V) exist as amixture of a Purine Derivative of Formula (V′) and a Purine Derivativeof Formula (Va′) wherein the amount of the Purine Derivative of Formula(V′) exceeds the amount of the Purine Derivative of Formula (Va′)

In another embodiment, the Purine Derivatives of Formula (V) exist as amixture of a Purine Derivative of Formula (V′) and a Purine Derivativeof Formula (Va′) wherein the amount of the Purine Derivative of Formula(Va′) exceeds the amount of the Purine Derivative of Formula (V′).

In another embodiment, the Purine Derivatives of Formula (Va) exist as aequal mixture of a Purine Derivative of Formula (V′) and a PurineDerivative of Formula (Va′).

In one embodiment, the Purine Derivatives of Formula (Va) exist as amixture of a Purine Derivative of Formula (V″) and a Purine Derivativeof Formula (Va″) wherein the amount of the Purine Derivative of Formula(V″) exceeds the amount of the Purine Derivative of Formula (Va″).

In another embodiment, the Purine Derivatives of Formula (Va) exist as amixture of a Purine Derivative of Formula (V″) and a Purine Derivativeof Formula (Va″) wherein the amount of the Purine Derivative of Formula(Va″) exceeds the amount of the Purine Derivative of Formula (V″).

In another embodiment, the Purine Derivatives of Formula (Va) exist as aequal mixture of a Purine Derivative of Formula (V″) and a PurineDerivative of Formula (Va″).

5.3 Methods for Making the Purine Derivatives

The Purine Derivatives can be made according to published methods (seeCristalli et al., J. Med. Chem. 35:2363-2369, 1992; Cristalli et al., J.Med. Chem. 37:1720-1726, 1994; Cristalli et al, J. Med. Chem.38:1462-1472, 1995; and Camaioni et al., Bioorg. Med. Chem. 5:2267-2275,1997), or by using the synthetic procedures outlined below in Schemes1-12.

Scheme 1 shows methods for making nucleoside intermediates that areuseful for making the Purine Derivatives of Formulas (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (II), (III), (IV) and (V).

wherein R₂ is as defined above for the Purine Derivatives of Formulas(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (II), (III), (IV) and(V).

The protected ribose compound of Formula 1 can be coupled with a purinecompound of Formula 2 using lithium hexamethyldisilazide andtrimethylsilyl triflate, followed by acetonide removal usingtrifluoroacetic acid to provide nucleoside intermediates of Formula 3and their corresponding other anomers of Formula 4. Similarly, theribose diacetate of Formula 5 can be coupled with a compound of Formula2 using lithium hexamethyldisilazide and trimethylsilyl triflate toprovide acetonide-protected nucleoside intermediates of Formula 6 andtheir corresponding other anomers of Formula 7.

Scheme 2 shows a method useful for making the adenosine intermediates ofFormula 8 which are useful for making the Purine Derivatives of Formulas(Ia), (Ib), (Ic), (Id) and (Ie).

where R¹ and R² are defined above herein for the Purine Derivatives.

The 6-chloroadenosine derivative of formula 3a is converted to its2′,3′-acetonide using acetone and 2,2-dimethoxypropane in the presenceof camphorsulfonic acid. The acetonide can be further derivatized usingan amine of formula R¹—NH₂ in the presence of base to provide compoundsof formula 8.

Scheme 3 shows a method useful for making the Purine Derivatives ofFormula (Ia)

where R¹ and R² are defined above herein for the Purine Derivatives ofFormula (Ia).

The adenosine intermediates of formula 8 can be converted to their5′-sulfonic acid analogs, which can then be chlorinated using thionylchloride to provide the corresponding 5′-chlorosulfonate intermediates.The chlorosulfonate intermediates can then be reacted with ammonia toprovide the corresponding 5′-sulfonamide intermediates. Acetonideremoval using TFA/water provides the Purine Derivatives of Formula (Ia).

Methodology useful for making Purine Derivatives of Formula (Ib) isdescribed in Scheme 4.

where R¹ and R² are defined above herein for the Purine Derivatives ofFormula (Ib).

The Adenosine intermediates of formula 8 can be converted to their5′-nitrate analogs using nitric acid in the presence of aceticanhydride, or other nitrating agents, such as MsCl/ONO₃ or nitrosoniumtetrafluoroborate. Acetonide removal using TFA/water provides PurineDerivatives of Formula (Ib).

Methodology useful for making the Purine Derivatives of Formula (Ic) isoutlined below in Scheme 5.

where R¹, R² and R⁵ are defined above herein for the Purine Derivativesof Formula (Ic).

The adenosine intermediates of formula 8 can be converted to their5′-alkoxyphosphonium perchlorate analogs using CCl₄—P(NMe₂)₃, thentreating the product of this reaction with ammonium perchlorate. Theintermediate 5′-alkoxyphosphonium perchlorates can subsequently bereacted with an amine of formula NH₂R⁵ to provide the 5′-amino analogs.Acetonide removal using TFA/water provides the Purine Derivatives ofFormula (Ic).

Methodology useful for making the Purine Derivatives of Formula (Id)wherein R³ is —CH₂OSO₃H is outlined in Scheme 6.

where R¹ and R² are defined above herein for the Purine Derivatives ofFormula (Id).

The adenosine intermediates of formula 8 can be treated with sulfurtrioxide-pyridine complex to provide the corresponding 5′-sulfonic acidpyridine salt intermediate. The pyridine salt intermediate can then beneutralized using NaOH or KOH, followed by acetonide removal usingTFA/water to provide the corresponding sodium or potassium salt,respectively, of the Purine Derivatives of Formula (Id) wherein R³ is—CH₂OSO₃H. Treatment of the sodium or potassium salt with strong aqueousacid, such as sulfuric or hydrochloric acid, provides the PurineDerivatives of Formula (Id) wherein R³ is —CH₂OSO₃H.

Methodology useful for making the Purine Derivatives of Formula (Id)wherein R³ is —ONO is outlined in Scheme 7.

where R¹ and R² are defined above herein for the Purine Derivatives ofFormula (Id).

The adenosine intermediates of formula 8 can be treated with nitrosoniumfluoroborate complex to provide the corresponding nitrosooxyintermediates. Acetonide removal using TFA/water provides the PurineDerivatives of Formula (Id) wherein R³ is —CH₂ONO.

Methodology useful for making the Purine Derivatives of Formula (Ie)wherein R³ is —OSO₂NH(C₁-C₁₀ alkyl), —OSO₂N(C₁-C₁₀ alkyl)₂, or—OSO₂NH-aryl, is outlined in Scheme 8.

where R¹ and R² are defined above herein for the Purine Derivatives ofFormula (Ie).

The adenosine intermediates of formula 8 can be reacted with sulfurtrioxide-pyridine complex to provide the corresponding 5′-sulfonic acidintermediates, which can subsequently be treated with thionyl chlorideto provide the intermediate 5′-chlorosulfonate intermediates. Thechlorosulfonate intermediates can then be reacted with an amine offormula H₂N—(C₁-C₁₀ alkyl), HN(C₁-C₁₀ alkyl)₂ or H₂N-aryl to provide thecorresponding 5′-sulfonamide intermediates. Acetonide removal usingTFA/water provides the Purine Derivatives of Formula (Ie) wherein R³ is—OSO₂NH(C₁-C₁₀ alkyl), —OSO₂N(C₁-C₁₀ alkyl)₂, or —OSO₂NH-aryl.

Methodology useful for making the Purine Derivatives of Formulas (II) isoutlined in Scheme 9.

where R¹ and R² are defined above herein for the Purine Derivatives ofFormula (II).

The 6-chloroadenosine derivatives of Formula 3a can be converted totheir 6-hydrazine derivatives of Formula 9 upon reacting with hydrazine.Compounds of Formula 9 can then be treated with a carbonyl compound offormula 10 to provide the Purine Derivatives of Formula (II).

Methodology useful for making the Purine Derivatives of Formula (III) isoutlined in Scheme 10.

where R¹, R² and R³ are defined above herein for the Purine Derivativesof Formula (III).

The compounds of Formula 3b can be protected as their 2′,3′-acetonidederivatives and their 5′-OH group can be converted to an R³ group usingmethodology well known to one skilled in the art of organic synthesis.Subsequent removal of the acetonide unit using TFA affords the6-chloroadenosine compounds of formula 12 which can be converted totheir 6-hydrazino derivatives of formula 13 using hydrazine. Thehydrazino compounds of formula 13 can then be treated with a carbonylcompound of formula 10 to provide the Purine Derivatives of Formula(III).

Methodology useful for making the Purine Derivatives of Formula (IV) isoutlined in Scheme 11.

where R¹ and R² are defined above herein for the Purine Derivatives ofFormula (IV).

The 6-chloroadenosine derivatives of Formula 3a can be converted totheir 6-hydrazine derivatives of Formula 9 upon reacting with hydrazine.Compounds of Formula 9 can then be treated with an aldehyde of formula14 to provide the Purine Derivatives of Formula (IV).

Methodology useful for making the Purine Derivatives of Formula (V) isoutlined in Scheme 12.

where R¹, R^(1a) and R² are defined above herein for the PurineDerivatives of Formula (V).

The 6-chloroadenosine derivatives of Formula 3a can be converted totheir 6-hydrazine derivatives of Formula 9 upon reacting with hydrazine.Compounds of Formula 9 can then be treated with a carbonyl compound offormula 15 to provide the Purine Derivatives of Formula (V).

Methodology useful for making the Purine Derivatives of Formula (Ih),wherein R¹ is cyclopent-1-ol-2-yl is outlined in Scheme 13.

2-Aminocyclopentanol (34) is reacted with carbobenzoyloxy chloride(CBZCl) to protect the amino functionality as its carbobenzoyloxyderivative. The OH group of the carbobenzoyloxy derivative is thenconverted to its corresponding triethylsilyl ether using triethylsilylchloride in the presence of imidazole. The carbobenzoyloxy protectinggroup is then removed via catalytic hydrogenation to provide aminecompound 35. Compound 35 is coupled with compound 36 in refluxingethanol to provide compound 37, which is subsequently nitrated usingacetic anhydride/nitric acid and then reacted with trifluroacetic acidto remove the acetonide group and provide compound 38.

Methodology useful for making the Purine Derivatives of Formula (Ih),wherein R¹ is cyclopent-1-ol-3-yl is outlined in Scheme 14.

3-Aminocyclopentanol (39) is reacted with CBZCl to protect the aminofunctionality as its carbobenzoyloxy derivative. The OH group of thecarbobenzoyloxy derivative is then converted to its correspondingtriethylsilyl ether using triethylsilyl chloride in the presence ofimidazole. The carbobenzoyloxy protecting group is then removed viacatalytic hydrogenation to provide amine compound 40. Compound 40 iscoupled with compound 36 in refluxing ethanol to provide compound 41,which is subsequently nitrated using acetic anhydride/nitric acid andthen reacted with trifluoroacetic acid to remove the acetonide group andprovide compound 42.

5.4 Therapeutic/Prophylactic Administration and Compositions of theInvention

Due to their activity, the Purine Derivatives are advantageously usefulin veterinary and human medicine. As described above, the PurineDerivatives are useful for: (i) treating or preventing a Condition in ananimal in need thereof; (ii) reducing an animal's rate of metabolism; or(iii) protecting an animal's heart against myocardial damage duringcardioplegia.

When administered to an animal, the Purine Derivatives can beadministered as a component of a composition that comprises aphysiologically acceptable carrier or vehicle. The present compositions,which comprise a Purine Derivative, can be administered orally. ThePurine Derivatives can also be administered by any other convenientroute, for example, by infusion or bolus injection, by absorptionthrough epithelial or mucocutaneous linings (e.g., oral, rectal, orintestinal mucosa) and can be administered together with anotherbiologically active agent. Administration can be systemic or local.Various known delivery systems, including encapsulation in liposomes,microparticles, microcapsules, and capsules, can be used.

Methods of administration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intracerebral, intravaginal, transdermal,rectal, by inhalation, or topical, particularly to the ears, nose, eyes,or skin. In some instances, administration will result in the release ofthe Purine Derivatives into the bloodstream. The mode of administrationcan be left to the discretion of the practitioner.

In one embodiment, the Purine Derivatives are administered orally.

In another embodiment, the Purine Derivatives are administeredintravenously.

In another embodiment, when the Purine Derivatives are used to reduce ananimal's rate of metabolism, the Purine Derivatives can be administeredby continuous intravenous infusion.

In other embodiments, it can be desirable to administer the PurineDerivatives locally. This can be achieved, for example, and not by wayof limitation, by local infusion during surgery, topical application,e.g., in conjunction with a wound dressing after surgery, by injection,by means of a catheter, by means of a suppository or enema, or by meansof an implant, said implant being of a porous, non-porous, or gelatinousmaterial, including membranes, such as sialastic membranes, or fibers.

In certain embodiments, it can be desirable to introduce the PurineDerivatives into the central nervous system, circulatory system orgastrointestinal tract by any suitable route, includingintraventricular, intrathecal injection, paraspinal injection, epiduralinjection, enema, and by injection adjacent to a peripheral nerve.Intraventricular injection can be facilitated by an intraventricularcatheter, for example, attached to a reservoir, such as an Ommayareservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler of nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the Purine Derivatives can be formulated as asuppository, with traditional binders and excipients such astriglycerides.

In another embodiment the Purine Derivatives can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1527-1533(1990) and Treat or prevent et al., Liposomes in the Therapy ofInfectious Disease and Cancer 317-327 and 353-365 (1989)).

In yet another embodiment the Purine Derivatives can be delivered in acontrolled-release system or sustained-release system (see, e.g.,Goodson, in Medical Applications of Controlled Release, supra, vol. 2,pp. 115-138 (1984)). Other controlled or sustained-release systemsdiscussed in the review by Langer, Science 249:1527-1533 (1990) can beused. In one embodiment a pump can be used (Langer, Science249:1527-1533 (1990); Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987);Buchwald et al., Surgery 88:507 (1980); and Saudek et al., N. Engl. J.Med. 321:574 (1989)). In another embodiment polymeric materials can beused (see Medical Applications of Controlled Release (Langer and Wiseeds., 1974); Controlled Drug Bioavailability, Drug Product Design andPerformance (Smolen and Ball eds., 1984); Ranger and Peppas, J.Macromol. Sci. Rev. Macromol. Chem. 2:61 (1983); Levy et al., Science228:190 (1935); During et al., Ann. Neural. 25:351 (1989); and Howard etal., J. Neurosurg. 71:105 (1989)).

In yet another embodiment a controlled- or sustained-release system canbe placed in proximity of a target of the Purine Derivatives, e.g., thespinal column, brain, colon, skin, heart, lung, or gastrointestinaltract, thus requiring only a fraction of the systemic dose.

The present compositions can optionally comprise a suitable amount of aphysiologically acceptable excipient.

Such physiologically acceptable excipients can be liquids, such as waterand oils, including those of petroleum, animal, vegetable, or syntheticorigin, such as peanut oil, soybean oil, mineral oil, sesame oil and thelike. The physiologically acceptable excipients can be saline, gumacacia, gelatin, starch paste, talc, keratin, colloidal silica, urea andthe like. In addition, auxiliary, stabilizing, thickening, lubricating,and coloring agents can be used. In one embodiment the physiologicallyacceptable excipients are sterile when administered to an animal. Watercan be a particularly useful excipient when the Purine Derivative isadministered intravenously. Saline solutions and aqueous dextrose andglycerol solutions can also be employed as liquid excipients,particularly for injectable solutions. Suitable physiologicallyacceptable excipients also include starch, glucose, lactose, sucrose,gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerolmonostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol and the like. The presentcompositions, if desired, can also contain minor amounts of wetting oremulsifying agents, or pH buffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions. aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment the composition is in the form of a capsule.Other examples of suitable physiologically acceptable excipients aredescribed in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R.Gennaro eds., 19th ed. 1995), incorporated herein by reference.

In one embodiment the Purine Derivatives are formulated in accordancewith routine procedures as a composition adapted for oral administrationto human beings. Compositions for oral delivery can be in the form oftablets, lozenges, aqueous or oily suspensions, granules, powders,emulsions, capsules, syrups, or elixirs for example. Orally administeredcompositions can contain one or more agents, for example, sweeteningagents such as fructose, aspartame or saccharin; flavoring agents suchas peppermint, oil of wintergreen, or cherry; coloring agents; andpreserving agents, to provide a pharmaceutically palatable preparation.Moreover, where in tablet or pill form, the compositions can be coatedto delay disintegration and absorption in the gastrointestinal tractthereby providing a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving a Purine Derivative are also suitable for orally administeredcompositions. In these latter platforms, fluid from the environmentsurrounding the capsule can be imbibed by the driving compound, whichswells to displace the agent or agent composition through an aperture.These delivery platforms can provide an essentially zero order deliveryprofile as opposed to the spiked profiles of immediate releaseformulations. A time-delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions can includestandard excipients such as mannitol, lactose, starch, magnesiumstearate, sodium saccharin, cellulose, and magnesium carbonate. In oneembodiment the excipients are of pharmaceutical grade.

In another embodiment the Purine Derivatives can be formulated forintravenous administration. Typically, compositions for intravenousadministration comprise sterile isotonic aqueous buffer. Wherenecessary, the compositions can also include a solubilizing agent.Compositions for intravenous administration can optionally include alocal anesthetic such as lignocaine to lessen pain at the site of theinjection. The compositions' components can be supplied eitherseparately or mixed together in unit dosage form, for example, as a drylyophilized powder or water-free concentrate in a hermetically sealedcontainer such as an ampule or sachette indicating the quantity ofPurine Derivative. Where the Purine Derivatives are to be administeredby infusion, they can be dispensed, for example, with an infusion bottlecontaining sterile pharmaceutical grade water or saline. Where thePurine Derivatives are administered by injection, an ampule of sterilewater for injection or saline can be provided so that the ingredientscan be mixed prior to administration.

The Purine Derivatives can be administered by controlled-release orsustained-release means or by delivery devices that are well known tothose of ordinary skill in the art. Such dosage forms can be used toprovide controlled- or sustained-release of one or more activeingredients using, for example, hydropropylmethyl cellulose, otherpolymer matrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, microspheres, or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled- or sustained-release formulations known to thoseskilled in the art, including those described herein, can be readilyselected for use with the active ingredients of the invention. Theinvention thus encompasses single unit dosage forms suitable for oraladministration such as, but not limited to, tablets, capsules, gelcaps,and caplets that are adapted for controlled- or sustained-release.

In one embodiment a controlled- or sustained-release compositioncomprises a minimal amount of a Purine Derivative to treat or preventthe Condition in a minimal amount of time. Advantages of controlled- orsustained-release compositions include extended activity of the drug,reduced dosage frequency, and increased patient compliance. In addition,controlled- or sustained-release compositions can favorably affect thetime of onset of action or other characteristics, such as blood levelsof the Purine Derivative, and can thus reduce the occurrence of adverseside effects.

Controlled- or sustained-release compositions can initially release anamount of a Purine Derivative that promptly produces the desiredtherapeutic or prophylactic effect, and gradually and continuallyrelease other amounts of the Purine Derivative to maintain this level oftherapeutic or prophylactic effect over an extended period of time. Tomaintain a constant level of the Purine Derivative in the body, thePurine Derivative can be released from the dosage form at a rate thatwill replace the amount of Purine Derivative being metabolized andexcreted from the body. Controlled- or sustained-release of an activeingredient can be stimulated by various conditions, including but notlimited to, changes in pH, changes in temperature, concentration oravailability of enzymes, concentration or availability of water, orother physiological conditions or compounds.

The amount of the Purine Derivative that is effective for treating orpreventing a Condition, reducing an animal's rate of metabolism, orprotecting an animal's heart against myocardial damage duringcardioplegia, can be determined by standard clinical techniques. Inaddition, in vitro or in vivo assays can optionally be employed to helpidentify optimal dosage ranges. The precise dose to be employed can alsodepend on the route of administration, and the seriousness of thecondition being treated and can be decided according to the judgment ofa health-care practitioner. Suitable effective dosage amounts, however,range from about 10 micrograms to about 5 grams about every 4 h,although they are typically about 500 mg or less per every 4 hours. Inone embodiment the effective dosage is about 0.01 mg, 0.5 mg, about 1mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg,about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg,about 1 g, about 1.2 g, about 1.4 g, about 1.6 g, about 1.8 g, about 2.0g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g,about 3.2 g, about 3.4 g, about 3.6 g, about 3.8 g, about 4.0 g, about4.2 g, about 4.4 g, about 4.6 g, about 4.8 g, and about 5.0 g, every 4hours. Equivalent dosages can be administered over various time periodsincluding, but not limited to, about every 2 hours, about every 6 hours,about every 8 hours, about every 12 hours, about every 24 hours, aboutevery 36 hours, about every 48 hours, about every 72 hours, about everyweek, about every two weeks, about every three weeks, about every month,and about every two months. The number and frequency of dosagescorresponding to a completed course of therapy can be determinedaccording to the judgment of a health-care practitioner. The effectivedosage amounts described herein refer to total amounts administered;that is, if more than one Purine Derivative is administered, theeffective dosage amounts correspond to the total amount administered.

The amount of a Purine Derivative that is effective for treating orpreventing a Condition, or protecting an animal's heart againstmyocardial damage during cardioplegia typically range from about 0.01mg/kg to about 100 mg/kg of body weight per day, in one embodiment, fromabout 0.1 mg/kg to about 50 mg/kg body weight per day, and in anotherembodiment, from about 1 mg/kg to about 20 mg/kg of body weight per day.

The amount of a Purine Derivative that is effective for reducing ananimal's rate of metabolism typically range from about 1 μg/kg to about10 mg/kg, in one embodiment, from about 0.1 mg/kg to about 5 mg/kg bodyweight per day, and in another embodiment, from about 1 mg/kg to about2.5 mg/kg of body weight per day.

When a Purine Derivative is a component of a solution that is useful formaintaining the viability of an organ ex vivo, the concentration of thePurine Derivative in the solution that is effective for maintaining theviability of the organ is between about 1 nM to about 1 mM.

The Purine Derivatives can be assayed in vitro or in vivo for thedesired therapeutic or prophylactic activity prior to use in humans.Animal model systems can be used to demonstrate safety and efficacy.

The present methods for treating or preventing a Condition, reducing ananimal's rate of metabolism, or protecting an animal's heart againstmyocardial damage during cardioplegia, can further compriseadministering another therapeutic agent to the animal being administereda Purine Derivative. In one embodiment the other therapeutic agent isadministered in an effective amount.

Effective amounts of the other therapeutic agents are well known tothose skilled in the art. However, it is well within the skilledartisan's purview to determine the other therapeutic agent's optimaleffective amount range. In one embodiment of the invention, where,another therapeutic agent is administered to an animal, the effectiveamount of the Purine Derivative is less than its effective amount wouldbe where the other therapeutic agent is not administered. In this case,without being bound by theory, it is believed that the PurineDerivatives and the other therapeutic agent act synergistically.

In one embodiment the other therapeutic agent is an anti-inflammatoryagent. Examples of useful anti-inflammatory agents include, but are notlimited to, adrenocorticosteroids, such as cortisol, cortisone,fluorocortisone, prednisone, prednisolone, 6a-methylprednisolone,triamncinolone, betamethasone, and dexamethasone; and non-steroidalanti-inflammatory agents (NSAIDs), such as aspirin, acetaminophen,indomethacin, sulindac, tolmetin, diclofenac, ketorolac, ibuprofen,naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamicacid, meclofenamic acid, piroxicam, meloxicam, nabumetone, rofecoxib,celecoxib, etodolac, and nimesulide.

In another embodiment the other therapeutic agent is an anti-diabeticagent. Examples of useful anti-diabetic agents include, but are notlimited to, glucagons; somatostatin; diazoxide; sulfonylureas, such astolbutamide, acetohexamide, tolazamide, chloropropamide, glybenclamide,glipizide, gliclazide, and glimepiride; insulin secretagogues, such asrepaglinide, and nateglinide; biguanides, such as metformiin andphenformin; thiazolidinediones, such as pioglitazone, rosiglitazone, andtroglitazone; and α-glucosidase inhibitors, such as acarbose andmiglitol.

In a further embodiment the other therapeutic agent is ananti-cardiovascular-disease agent. Examples of usefulanti-cardiovascular-disease agents include, but are not limited to,carnitine; thiamine; lidocaine; amiodarone; procainamide; mexiletine;bretylium tosylate; propanolol; sotalol; and muscarinic receptorantagonists, such as atropine, scopolamine, homatropine, tropicamide,pirenzipine, ipratropium, tiotropium, and tolterodine.

In another embodiment the other therapeutic agent is an analgesic agent.Examples of useful analgesic agents include, but are not limited to,buprenorphine, meperidine, morphine, codeine, propoyxphene, fentanyl,sufentanil, etorphine hydrochloride, hydrocodone, hydromorphone,nalbuphine, butorphanol, oxycodone, aspirin, ibuprofen, naproxen sodium,acetaminophen, xylazine, metedomidine, carprofen, naprosin, andpentazocine.

In a specific embodiment, the other therapeutic agent is buprenorphine.

In another embodiment, the other therapeutic agent is an antiemeticagent. Examples of useful antiemetic agents include, but are not limitedto, metoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, ondansetron, granisetron,hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron,benzquinamide, bietanautine, bromopride, buclirine, clebopride,cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine,thioproperazine, tropisetron, or mixtures thereof.

A Purine Derivative and the other therapeutic agent can act additivelyor, in one embodiment, synergistically. In one embodiment, a PurineDerivative is administered concurrently with another therapeutic agent.In one embodiment, a composition comprising an effective amount of aPurine Derivative and an effective amount of another therapeutic agentcan be administered. Alternatively, a composition comprising aneffective amount of a Purine Derivative and a different compositioncomprising an effective amount of another therapeutic agent can beconcurrently administered. In another embodiment, an effective amount ofa Purine Derivative is administered prior or subsequent toadministration of an effective amount of another therapeutic agent. Inthis embodiment, the Purine Derivative is administered while the othertherapeutic agent exerts its therapeutic effect, or the othertherapeutic agent is administered while the Purine Derivative exerts itspreventative or therapeutic effect for treating or preventing aCondition, reducing an animal's rate of metabolism or protecting ananimal's heart against myocardial damage during cardioplegia.

A composition of the invention can be prepared using a method comprisingadmixing a Purine Derivative and a physiologically acceptable carrier orexcipient. Admixing can be accomplished using methods well known foradmixing a compound (or salt) and a physiologically acceptable carrieror excipient.

5.6 Therapeutic or Prophylactic Uses of the Purine Derivatives 5.6.1Treatment or Prevention of a Cardiovascular Disease

A cardiovascular disease can be treated or prevented by administrationof an effective amount of a Purine Derivative.

Cardiovascular diseases that can be treated or prevented byadministering an effective amount of a Purine Derivative include, butare not limited to, atherosclerosis, congestive heart failure,circulatory shock, cardiomyopathy, cardiac transplant, cardioplegia, anda cardiac arrhythmia.

In one embodiment, the cardiovascular disease is a cardiac arrhythmia,congestive heart failure, circulatory shock or cardiomyopathy.

In one embodiment, the cardiac arrhythmia is a tachycardia or anidiotopic arrhythmia.

In another embodiment, the methods for treating a cardiovascular diseaseare useful for converting a cardiac arrhythmia to a normal sinus rhythm.

In still another embodiment, the tachycardia is atrial fibrillation,supraventricular tachycardia, atrial flutter, paroxysmalsupraventricular tachycardia, paroxysmal atrial tachycardia, sinustachycardia, atrioventricular nodal reentry tachycardia, or tachycardiacaused by Wolff-Parkinson-White Syndrome.

In a further embodiment, the methods for treating a tachycardia areuseful for lowering the animal's ventricular rate to a rate of not lessthan about 40 beats per minute. In a specific embodiment, the methodsare useful for lowering an animal's ventricular rate to a rate of fromabout 60 beats per minute to about 100 beats per minute.

5.6.2 Protecting an Animal's Heart Against Myocardial Damage DuringCardioplegia

In one embodiment, the invention provides methods for inducingcardioplegia comprising administering to an animal in need thereof aneffective amount of a cardioplegia-inducing agent and a PurineDerivative. Cardioplegia-inducing agents useful in the present inventioninclude, but are not limited to, potassium chloride, procaine,lidocaine, novocaine, bupivocaine, nicorandil, pinacidil, halothane, St.Thomas solution, Fremes solution, 2,3-butanedione monoxime, and esmolol.

In one embodiment, the cardioplegia-inducing agent is lidocaine.

In one embodiment, a cardioplegia-inducing agent and a Purine Derivativeare present within the same composition. The present methods forinducing cardioplegia are useful for preventing or minimizing myocardialdamage from occurring during cardioplegia.

In still another embodiment, the invention provides methods forprotecting an animal's heart against myocardial damage duringcardioplegia, the method comprising administering to an animal in needthereof an effective amount of:

(a) a cardioplegia-inducing agent; and

(b) a Purine Derivative.

In one embodiment, the cardioplegia-inducing agent is administered priorto the administration of the Purine Derivative.

In another embodiment, Purine Derivative is administered prior to theadministration of the cardioplegia-inducing agent.

In a further embodiment, the cardioplegia-inducing agent and the PurineDerivative are administered concurrently.

In another embodiment, the cardioplegia-inducing agent and the PurineDerivative are administered such that the Purine Derivative exerts itsprophylactic effect of protection against myocardial damage while thecardioplegia-inducing agent exerts its cardioplegic effect.

5.63 Treatment or Prevention of a Neurological Disorder

A neurological disorder can be treated or prevented by administration ofan effective amount of a Purine Derivative.

Neurological disorders that can be treated or prevented by administeringan effective amount of a Purine Derivative include, but are not limitedto, a seizure disorder, such as epilepsy; pain, including acutepostoperative pain, cancer pain, neuropathic pain, pain resulting fromsurgery, labor pain during childbirth, a psychogenic pain syndrome, andheadache, including migraine headache and cluster headache; delirium anddementia, such as Lewy body dementia, Alzheimer's disease, Pick'sdisease, or a Creutzfeldt-Jakob disease; a sleep disorder, such asinsomnia, hypersomnia, a sleep apnea syndrome, restless-leg syndrome, ora parasomnia; a cranial nerve disorder, such as Bell's palsy; a disorderof movement, such as tremor, dystonia, Tourette's Syndrome, myoclonus,Huntington's disease, cortico basal degeneration, chorea, a drug-inducedmovement disorder, progressive supranuclear palsy, Parkinson's disease,or a Parkinsonian Syndrome, such as multiple system atrophy, Wilson'sdisease or multi-infarct state; a demyelinating disease, such asmultiple sclerosis or amyotrophic lateral sclerosis; a neuro-musculardisease, such as muscular dystrophy; a cerebrovascular disease, such asstroke; a neuroopthalmic disorder; and a psychiatric disorder, includingbut not limited to, somatoform disorders, such as hypochondriasis orbody dysmorphic disorder; dissociation disorders, such as panicdisorder, phobic disorders, or obsessive-compulsive disorders; mooddisorders, such as depression or bipolar-disorders; personalitydisorders; psychosexual disorders; suicidal behavior; schizophrenia;brief psychotic disorder; and delusional disorder.

In one embodiment, the neurological disorder treated or prevented isepilepsy, pain, or stroke.

In one embodiment, the present methods for treating pain furthercomprise the administration of an additional analgesic agent. In aspecific embodiment, the additional analgesic agent is buprenorphine.

5.6.4 Treatment or Prevention of an Ischemic Condition

An ischemic condition can be treated or prevented by administration ofan effective amount of a Purine Derivative.

Ischemic conditions that can be treated or prevented by administering aneffective amount of a Purine Derivative include, but are not limited to,stable angina, unstable angina, myocardial ischemia, hepatic ischemia,mesenteric artery ischemia, intestinal ischemia, myocardial infarction,critical limb ischemia, chronic critical limb ischemia, erebralischemia, acute cardiac ischemia, and an ischemic disease of the centralnervous system, such as stroke or cerebral ischemia.

In one embodiment, the ischemic condition is myocardial ischemia, stableangina, unstable angina, stroke, ischemic heart disease or cerebralischemia.

5.6.5 Treatment or Prevention of a Reperfusion Injury

A reperfusion injury can be treated or prevented by administration of aneffective amount of a Purine Derivative. Reperfusion injury can resultfollowing a naturally occurring episode, such as a myocardial infarctionor stroke, or during a surgical procedure where blood flow in vessels isintentionally or unintentionally blocked.

Reperfusion injuries that can be treated or prevented by administeringan effective amount of a Purine Derivative include, but are not limitedto, intestinal reperfusion injury, myocardial reperfusion injury; andreperfusion injury resulting from cardiopulmonary bypass surgery,thoracoabrominal aneurysm repair surgery, carotid endaretectomy surgery,or hemorrhagic shock.

In one embodiment, the reperfusion injury results from cardiopulmonarybypass surgery, thoracoabrominal aneurysm repair surgery, carotidendarerectomy surgery or hemorrhagic shock.

5.6.6 Treatment or Prevention of Diabetes

Diabetes can be treated or prevented by administration of an effectiveamount of a Purine Derivative.

Types of diabetes that can be treated or prevented by administering aneffective amount of a Purine Derivative include, but are not limited to,Type I diabetes (Insulin Dependent Diabetes Mellitus), Type II diabetes(Non-Insulin Dependent Diabetes Mellitus), gestational diabetes,insulinopathy, diabetes due to pancreatic disease, diabetes associatedwith another endocrine disease (such as Cushing's Syndrome, acromegaly,pheochromocytoma, glucagonoma, primary aldosteronism orsomatostatinoma), Type A insulin resistance syndrome, Type B insulinresistance syndrome, lipatrophic diabetes, and diabetes induced byβ-cell toxins.

In one embodiment, the diabetes is Type I diabetes mellitus.

In another embodiment, the diabetes is Type II diabetes mellitus.

5.6.7 Methods for Reducing an Animal's Rate of Metabolism

In one embodiment, the invention provides methods for reducing ananimal's rate of metabolism comprising administering to an animal inneed thereof an amount of a Purine Derivative that is effective to slowthe animal's rate of metabolism.

Reducing an animal's rate of metabolism is useful for slowing ananimal's heart rate during heart surgery; protecting an animal's tissuefrom damage during surgery, particular heart or brain surgery; reducingintracranial hypertension caused by brain injury in an animal; orinducing hibernation in an animal.

Accordingly, the present invention encompasses methods for slowing ananimal's heart rate during heart surgery; protecting an animal's tissuefrom damage during surgery, particular heart or brain surgery; reducingintracranial hypertension caused by brain injury in an animal; orinducing hibernation in an animal, the methods comprising administeringan effective amount of a Purine Derivative to an animal in need thereof.

Reducing an animal's rate of metabolism is also useful for reducing ananimal's rate of oxygen consumption. Accordingly, the present inventionprovides methods for reducing the rate of an animal's oxygenconsumption, the method comprising administering to an animal in needthereof an amount of a Purine Derivative that is effective to reduce theanimal's rate of oxygen consumption. An animal's oxygen supply might becompromised due to: (i) a medical procedure, such as heart surgery,brain surgery, organ transplantation, mechanical occlusion of thevascular supply, or vascular stenosis; (ii) a disorder or medicalcondition such as ischemia, a respiratory disorder, respiratory failure,a pulmonary disorder, anemia, anaphylactic shock, hemmorhagic shock,dehydration, compartment syndrome, intravascular thrombus, septic shock,cystic fibrosis, lung cancer, stroke, a burn, or internal bleeding;(iii) an injury such as drowning, a crush injury to one or more limbs,choking, or suffocation; (iv) a compromised airway due to asthma, atumor, a lung injury or a tracheal injury; (v) an external compressionof one or more blood vessels; or (vi) an intrinsic obstruction of one ormore blood vessels. Reducing an animal's rate of oxygen consumption isuseful for treating or preventing tissue damage or stroke, resultingfrom an inadequate supply of oxygen to a cell, a tissue, an organ or anorgan system.

In one embodiment, an animal's rate of oxygen consumption is reduced toincrease emergency recitation in an injured animal.

In another embodiment, an animal's rate of oxygen consumption is reducedprior to and during heart surgery. In a specific embodiment, the animalis a human child undergoing pediatric heart surgery.

In another embodiment, a animal's rate of oxygen consumption is reducedto treat respiratory failure in an animal.

In one embodiment, an animal's rate of oxygen consumption is reduced toaid tissue metabolism in an animal whose respiration and ventilation isfacilitated by a ventilator. In a specific embodiment, the animal whoserespiration and ventilation is facilitated by a ventilator is ageriatric human. In another specific embodiment, the animal whoserespiration and ventilation is facilitated by a ventilator is apremature human infant.

In one embodiment, an organ can be stored ex vivo in a compositioncomprising an effective amount of a Purine Derivative. The compositionis useful for preserving an organ's viability after being removed from adonor and before the organ is transplanted in a recipient. In oneembodiment, the donor and recipient are the same.

In another embodiment, an effective amount of a Purine Derivative can beadministered to an animal awaiting organ transplantation to reduce theanimal's rate of oxygen consumption prior to or during organtransplantation.

Reducing an animal's rate of metabolism is also useful for reducing ananimal's core body temperature. Accordingly, the present inventionprovides methods for reducing an animal's core body temperature, themethod comprising administering to an animal in need thereof an amountof a Purine Derivative that is effective to reduce the animal's corebody temperature.

In one embodiment, the animal's core body temperature is reduced to atemperature from about 4° C. to about 34° C. In certain embodiments, theanimal's core body temperature is reduced to about 34° C., to about 30°C., to about 25° C., to about 20° C., to about 15° C., to about 10° C.,or to about 4° C.

In a specific embodiment, an animal's core body temperature is reducedto induce therapeutic hypothermia.

5.6.8 Treatment or Prevention of Obesity

Obesity can be treated or prevented by administration of an effectiveamount of a Purine Derivative.

Types of obesity that can be treated or prevented by administering aneffective amount of a Purine Derivative include, but are not limited to,android obesity, gynoid obesity, abdominal obesity, age-related obesity,diet-induced obesity, fat-induced obesity, hypothalamic obesity, morbidobesity, multigenic obesity, and visceral obesity.

In one embodiment, the obesity is android obesity.

5.6.9 Treatment or Prevention of a Wasting Disease

In one embodiment, the invention provides methods for treating orpreventing a wasting disease, comprising administering to an animal inneed thereof an amount of a a Purine Derivative that is effective totreat or prevent the wasting disease.

Types of wasting diseases that can be treated or prevented byadministering an effective amount of a Purine Derivative include, butare not limited to chronic wasting disease, cancer wasting syndrome, andAIDS wasting syndrome.

6. EXAMPLES

Materials: [³H]NECA was obtained from Du Pont NEN, Dreieich, Germany.Other unlabeled adenosine receptor agonists and antogonists can beobtained from RBI, Natick, Mass. The 96-well microplate filtrationsystem (MultiScreen MAFC) was obtained from Millipore, Eschbom, Germany.Penicillin (100 U/mL), streptomycin (100 μg/mL), L-glutamine and G418were obtained from Gibco-Life Technologies, Eggenstein, Germany. Othermaterials can be obtained as described in Klotz et al., J. Biol. Chem.,260:14659-14664, 1985; Lohse et al., Naunyn-Schmiedeberg's Arch.Pharmacol., 336:204-210, 1987; and Klotz et al., Naunyn-Schmiedeberg'sArch. Pharmacol., 357:1-9, 1998.

General Methods Proton nuclear magnetic resonance (NMR) spectra wereobtained from Varian 300 MHz spectrophotometer and chemical shifts arereported in parts per million. Compounds were characterized on the basisof NMR and Mass spectral (MS) data. 6-Chloroadenosine and2′,3′,5′-triacetoxy-2,6-dichloroadenosine were purchased from TRC,Ontario, Canada. 2′,3′-Isopropylideneadenosine and 2-chloroadenosinewere purchased from ACROS Organic, USA.

6.1 Example 1 Synthesis of Compound 16

2-Chloro-N⁶-cyclopentyladenosine-2′,3′,5′-triacetoxy-2,6-dichloroadenosine(1.5 g) and cyclopentylamine (8 eq.) were diluted with ethanol (50 eq.)and the resulting solution was heated at reflux for about 15 hours, thencooled to room temperature and concentrated in vacuo to provide a cruderesidue which was diluted with a mixture of ethyl acetate and water andtransferred to a separatory funnel. The organic layer was separated,dried over sodium sulfate and concentrated in vacuo to provide a cruderesidue which was purified using flash column chromatography on silicagel (8% MeOH—dichloromethane as eluent) to provide2-chloro-N⁶-cyclopentyladenosine (0.948 g). MS m/z 370.32 [M+H]⁺.

2′,3′-Isopropylidene-2-chloro-N⁶-cyclopentyladenosine:2-chloro-N⁶-cyclopentyladenosine (900 mg, as prepared in the previousstep) and 2,2-dimethoxypropane (10 eq.) were diluted with acetone (15mL) and to the resulting solution was added D-camphorsulphonic acid (1eq) and the resulting reaction was allowed to stir at room temperaturefor 2 hr. The resulting reaction mixture was concentrated in vacuo,diluted with a mixture of saturated aqueous NaHCO₃ and ethyl acetate,and transferred to a separatory funnel. The organic layer was separated,dried over sodium sulfate and concentrated in vacuo to provide a cruderesidue which was purified using flash column chromatography on silicagel (using 5% MeOH—dichloromethane as eluent) to provide2′,3′-Isopropylidene-2-chloro-N⁶-cyclopentyladenosine (0.905 g). ¹H NMR(CDCl₃, 300 MHz): δ 1.36 (s, 3H), 1.62 (s, 3H), 1.66-2.16 (m, 9H), 3.78(d, J=12.9 Hz, 1H), 3.98 (d, J=12.9 Hz, 1H), 4.51 (bs, 1H), 4.55-4.60(m, 1H), 5.09-5.17 (m, 2H), 5.81 (bs, 1H), 7.25 (s, 1H), 7.89 (s, 1H).

2′,3′-Isopropylidene-2-chloro-N⁶-cyclopentyladenosine-5′-nitrate: Asolution of nitric acid (2.0 mL, 60%) was added slowly over a period of30 minutes to acetic anhydride (16.0 mL) at −10 to 10° C. (usingacetonitrile-CO₂ cooling bath) and the reaction mixture was allowed tostir at −10 to 10° C. for 10 minutes. The reaction mixture was thencooled to −30° C. and then a solution of2′,3′-Isopropylidene-2-chloro-N⁶-cyclopentyladenosine (655 mg, 0.0016mol, as prepared in the previous step) in acetic anhydride (8.0 mL) wasadded slowly. When addition was complete, the resulting reaction wasallowed to warm to −5° C. and monitored using TLC (solvent 5%MeOH—CH₂Cl₂ or 70% EtOAc-hexane). When the reaction was complete, thereaction mixture was poured slowly into an ice cold mixture of saturatedaqueous NaHCO₃ (300 equivalent in 75 mL water) and ethyl acetate (60mL). The organic layer was separated and the aqueous layer was backextracted with ethyl acetate. The combined organic layers were washedwith water, dried over sodium sulfate, and concentrated in vacuo toprovide a crude residue. The crude residue was purified using flashcolumn (5% methanol-dichloromethane as eluent) to provide2′,3′-Isopropylidene-2-chloro-N⁶-cyclopentyladenosine-5′-nitrate (0.435g). ¹H NMR (CDCl₃, 300 MHz): δ 1.38 (s, 3H), 1.59 (s, 3H), 1.66-2.13 (m,9H), 4.50-4.55 (m, 1H), 4.71-4.83 (m, 2H), 5.14-5.17 (m, 1H), 5.31 (d,J=5.7 Hz, 1H), 6.04 (s, 1H), 7.24 (s, 1H), 7.81 (s, 1H). MS m/z 455.44[M+H]⁺.

Compound 16:2′,3′-Isopropylidene-2-chloro-N⁶-cyclopentyladenosine-5′-nitrate (0.435g, as prepared in the previous step) was diluted with TFA (20 mL) andwater (5 mL) and the resulting solution was allowed to stir for 30minutes. The resulting reaction mixture was concentrated in vacuo andthe resulting residue was diluted with water (10 mL) and the resultingsolution was concentrated in vacuo. The crude residue obtained wasdiluted with ethyl acetate, transferred to a separatory funnel, washedwith saturated aqueous sodium bicarbonate, dried over sodium sulfate andconcentrated in vacuo. The crude residue obtained was purified usingflash column chromatography on silica gel (using 10%methanol-dichloromethane as eluent) to provide Compound 16 (0.250 g). ¹HNMR (DMSO-d₆, 300 MHz): δ 1.52-1.95 (m, 9H), 4.13-4.24 (m, 2H),4.55-4.58 (m, 1H), 4.73-4.85 (m, 2H), 5.50 (bs, 1H), 5.61 (bs, 1H), 5.84(d, J=5.1 Hz, 1H), 8.33 (bs, 2H), MS m/z 414.85 [M+H]⁺.

6.2 Example 2 Synthesis of Compound 17

N⁶-Cyclopentyladenosine: A solution of 6-chloroadenosine (43 g) andcyclopentylamine (5 eq.) in ethanol (50 eq.) was heated at reflux for 3hours then cooled to room temperature. The resultant reaction mixturewas concentrated in vacuo and the resultant residue was diluted withwater (400 ml) and ethyl acetate (400 ml). The eoganic layer wasseparated and the aqueous layer was extracted into ethyl acetate (2×400ml). The combined organic layers were washed with water (2×200 ml),dried over sodium sulfate, concentrated in vacuo and dried under vacuumto provide a solid which was suspended in MeOH (400 mL), filtered anddried to provide N6-cyclopentyladenosine (43.8 g).

2′,3′-isopropylidene-N⁶-cyclopentyladenosine: N⁶-cyclopentyladenosine(43 g) was diluted with acetone (75 eq.) and to the resultant solutionwas added 2,2-dimethoxypropane (5 eq.), followed by D-camphorsulphonicacid (1 eq) and the resultant reaction was allowed to stir at roomtemperature for 3 hours. The resultant reaction mixture was concentratedin vacuo and the resultant residue was diluted with ethyl acetate, thenneutralized to pH 7.0 using concentrated aqueous NaHCO₃. The organiclayer was separated, dried over sodium sulfate, concentrated in vacuoand dried under vacuum to provide a solid which was suspended in hexane(250 mL), filtered, washed with hexane and dried under vacuum to provide2′,3′-isopropylidene-N⁶-cyclopentyl adenosine (43 g).

2′,3′-isopropylidene-N⁶-cyclopentyladenosine-5′-nitrate: Aceticanhydride (22 eq) was slowly added to a stirred solution of nitric acid(5 eq., 63%) at −10° C. (acetonitrile-CO₂ bath used for cooling) over aperiod of 4 hours with the reaction temperature maintained at −5 to 5°C. during the addition. The resultant solution was cooled to −20° C. anda solution of 2′,3′-isopropylidene-N⁶-cyclopentyladenosine (18.250 gm,0.048 mol) in acetic anhydride (37 mL, 8 eq.) was added slowly. Theresultant reaction was allowed to stir at −15 to −5° C. for 1 hour andthe resultant reaction mixture was slowly poured slowly into an ice-coldsolution of aqueous NaHCO₃ (168 gm in 800 mL water) and ethyl acetate(350 mL) and the resultant solution was allowed to stir for 5 minutes.The organic layer was separated and the aqueous layer was extractedusing ethyl acetate (350 mL). The combined organic layers were washedwith water, and dried over sodium sulfate, concentrated in vacuo andpurified using flash column chromatograpy on silica gel using 70% ethylacetate-hexane as eluent to provide2′,3′-isopropylidene-N⁶-cyclopentyladenosine-5′-nitrate (14.9 g).

Compound 17: 2′,3′-isopropylidene-N⁶-cyclopentyladenosine-5′-nitrate(4.8 g) was diluted with a mixture of TFA (20 mL) and water (5 mL) andthe resultant reaction was allowed to stir for 30 minutes at roomtemperature. The resultant reaction mixture was concentrated in vacuoand the resultant residue was diluted with water (10 mL) andconcentrated in vacuo. The resultant residue was diluted with ethylacetate and washed with saturated aqueous sodium bicarbonate, and theorganic layer was dried over sodium sulfate and concentrated in vacuo toprovide a white solid residue which was dried under vacuum and thenrecrystallized from cold ethanol to provide Compound 17 (3.1 gm). ¹H-NMR(DMSO-d₆): δ 1.49-1.58 (m, 4H), 1.66-1.72 (m, 2H), 1.89-1.94 (m, 2H),4.12-4.17 (m, 1H), 4.28-4.33 (m, 1H), 4.48 (bs, 1H), 4.65-4.87 (m, 3H),5.5 (d, J=5.1 Hz, 1H), 5.63 (d, J=5.7 Hz, 1H), 5.91 (d, J=5.1 Hz, 1H),7.75 (d, J=7.5 Hz, 1H), 8.17 (bs, 1H), 8.30 (s, 1H); MS (ES⁺): m/z381.35 (M+1); Anal. Calcd for C₁₅H₂₀N₆O₆: C, 47.37; H, 5.30; N, 22.10.Found: C, 47.49; H, 5.12; N, 21.96.

6.3 Example 3 Synthesis of Compound 18

2′,3′-Isopropylidene-adenosine: A solution of adenosine (43 g) and2,2-dimethoxypropane (5 eq.) in acetone (75 eq.) was treated withD-camphorsulphonic acid (1 eq) at and the resulting reaction was allowedto stir for 3 hr. The reaction mixture was concentrated in vacuo anddiluted with a mixture of saturated aqueous NaHCO₃ (250 mL) and ethylacetate (250 mL). The resulting solution was transferred to a separatoryfunnel and the organic layer was separated, dried over sodium sulfate,and concentrated in vacuo to provide a solid residue. The solid residuewas suspended in hexane, filtered, washed with hexane and dried toprovide 2′,3′-Isopropylidene-adenosine (43 g). ¹H NMR (DMSO-d₆, 300MHz): δ 4.12-4.17 (m, 1H), 4.22-4.26 (m, 1H), 4.59 (d, J=4.8 Hz, 1H),4.74-4.85 (m, 2H), 5.49-5.52 (m, 1H), 5.51 (d, J=5.1 Hz, 1H), 5.84 (d,J=5.1 Hz, 1H), 7.85 (s, 2H), 8.33 (s, 1H). MS t/z 347.11 [M+H]⁺.

2′,3′-Isopropylidene-adenosine-5′-nitrate: A solution of nitric acid(19.8 mL, 60%) was added slowly over a period of 30 minutes to aceticanhydride (100 mL) at −10 to 10° C. (using acetonitrile-CO₂ coolingbath) and the reaction mixture was allowed to stir at −10 to 10° C. for10 minutes. The reaction mixture was then cooled to −30° C. and then asolution of 2′,3′-Isopropylidene-adenosine (5.945 g, as prepared in theprevious step) in acetic anhydride (49.3 mL) was added slowly. Whenaddition was complete, the resulting reaction was allowed to warm to −5°C. and monitored using TLC (solvent 5% MeOH—CH₂Cl₂ or 70% EtOAc-hexane).When the reaction was complete, the reaction mixture was poured slowlyinto an ice cold mixture of saturated aqueous NaHCO₃ (300 equivalent in500 mL water) and ethyl acetate (250 mL). The organic layer wasseparated and the aqueous layer was back extracted with ethyl acetate.The combined organic layers were washed with water, dried over sodiumsulfate, and concentrated in vacuo to provide a crude residue. The cruderesidue was purified using flash column (5% methanol-dichloromethane aseluent) to provide 2′,3′-Isopropylidene-adenosine-5′-nitrate (4.850 g).¹H NMR (DMSO-d₆, 300 MHz): δ 1.31 (s, 3H), 1.52 (s, 3H), 1.53-1.96 (m,9H), 4.41-4.43 (m, 1H), 4.68-4.74 (m, 1H), 4.80-4.86 (m, 1H), 5.14-5.16(m, 1H), 5.41 (d, J=6 Hz, 1H), 6.23 (s, 1H), 7.80 (s, 1H), 8.21 (s, 1H),8.29 (s, 1H). MS m/z 421.09 [M+H]⁺.

Compound 18: 2′,3′-Isopropylidene-adenosine-5′-nitrate (4.8 g, asprepared in the previous step) was diluted with 4:1 mixture of TFA (20mL) and water (5 mL) and the resulting solution was allowed to stir atrt for 30 minutes. The resulting reaction mixture was concentrated invacuo and the resulting residue was diluted with water (10 mL) andconcentrated in vacuo to provide a residue which was diluted with ethylacetate (20 mL). The resulting solution was washed with saturatedaqueous sodium bicarbonate, dried over sodium sulfate and concentratedin vacuo to provide a white solid residue which was further dried invacuo and then recrystallized from ethanol to provide Compound 18 (3.1g). ¹H NMR (DMSO-d₆, 300 MHz): δ 1.53-1.96 (m, 9H), 4.12-4.17 (m, 1H),4.28-4.33 (m, 1H), 4.65-4.70 (m, 1H), 4.74-4.87 (m, 1H), 5.50 (d, J=5.1Hz, 1H), 5.62 (d, J=5.7 Hz, 1H), 5.90 (d, J=5.1 Hz, 1H), 7.74 (d, J=7.5Hz, 1H), 8.17 (s, 1H), 8.30 (s, 1H). MS m/z 381.04 [M+H]⁺.

6.4 Example 4 Synthesis of Compound 19

Using the method described in Example 3 and using commercially available2-chloroadenosine in place of adenosine in step 1, Compound 19 wasprepared.

6.5 Example 5 Synthesis of Compound 21

N⁶-Hydrazinoadenosine: A mixture of 6-chloroadenosine (1 g, 3.5 mmol)and hydrazine monohydrate (5 mL) in MeOH (10 mL) was stirred at 50° C.for 1 hr. The reaction mixture was allowed to cool to room temperatureand was then concentrated in vacuo to provide a crude residue which wassuspended in MeOH and (10 mL) and stirred at room temperature. The solidproduct that separated out from the suspension was filtered, washed withMeOH and dried in vacuo to provide N⁶-hydrazinoadenosine (970 mg) whichwas used without further purification.

Compound 21: A suspension of N⁶-hydrazinoadenosine (50 mg, prepared asdescribed in the previous step) and cyclopentanealdehyde (0.26 mmol) inmethanol (5 mL) was heated at reflux for 15 minutes and the reactionmixture was cooled to room temperature, then concentrated in vacuo toprovide a crude residue which was purified using silica gel flashchromatography (10% methanol/dichloromethane eluent) to provide compound21 (52 mg). MS m/z 363.11 [M+H]⁺.

6.6 Example 6 Synthesis of Compound 22

2,6-Dihydrazinoadenosine: A mixture of2,6-chloro-2′,3′5′-triacetyladenosine (0.150 gm, 0.33 mmol) andhydrazine monohydrate (2 mL) in MeOH (5 mL) was heated at reflux forabout 8 hours. The reaction mixture was cooled to room temperature andconcentrated in vacuo, and the resulting residue was suspended in MeOH(5 mL) and stirred at room temperature for 1 hour. The solid productwhich separated out from the suspension was filtered, washed with MeOHand dried in vacuo to provide 2,6-dihydrazinoadenosine (65 mg), whichwas used without further purification.

Compound 22: A mixture of 2,6-dihydrazinoadenosine (60 mg, prepared asdescribed in the previous step) and cyclopentanaldehyde (0.1 mL) inmethanol (5 mL) was heated at reflux for 15 minutes. The reactionmixture was then cooled to room temperature and concentrated in vacuo toprovide a crude residue which was purified using silica gel flashchromatography (10% methanol/dichloromethane eluent) to provide compound22 (48 mg). MS m/z 473.25 [M+H]⁺.

6.7 Example 7 Synthesis of Compound 23 (Sodium Salt)

A mixture of 2′,3′-isopropylidene-N⁶-cyclopentyladenosine (1 g, 0.0026mol, prepared as set forth in Example 1) and sulfur trioxide-pyridinecomplex (0.0039 mol) in DMF (17 mL) was stirred at room temperature forabout 18 hours. The DMF was removed in vacuo and the resulting residuewas dried in vacuo. The dried residue was diluted with water (25 mL),neutralized to pH 7.0 using NaOH (1N) and concentrated in vacuo toprovide a crude residue which was diluted with an solution of TFA (80%solution in water, 50 mL). The resulting solution was allowed to stir at25° C. for 30 minutes and the reaction mixture was concentrated in vacuoto afford a crude residue which was diluted with water (10 mL) andconcentrated in vacuo. The crude compound obtained was recrystallizedfrom acetone—water to provide compound 23 (sodium salt) (805 mg). ¹HMNR(DMSO-d₆, 300 MHz): 1.53-1.96 (m, 9H), 3.78-4.10 (m, 4H), 4.43-4.54 (m,2H), 5.90 (d, J=5.1 Hz, 1H), 8.23 (s, 1H), 8.46 (s, 1H). MS m/z 416.20[M+H]⁺.

6.8 Example 8 Synthesis of Compound 24 (Sodium Salt)

Using the method described in Example 8 and substituting2′,3′-isopropylidene-adenosine (prepared as set forth in Example 3) for2′,3′-isopropylidene-N⁶-cyclopentyladenosine, Compound 24 (sodium salt)was prepared. ¹HMNR (DMSO-d₆, 300 MHz): 3.83-3.99 (m, 2H), 4.10-4.14 (m,2H), 4.50-4.54 (m, 1H), 5.94 (d, J=6 Hz, 1H), 8.5 (s, 1H), 8.73 (s, 1H),9.50 (bs, 2H). MS m/z 348.05 [M+H]⁺.

6.9 Example 9 Cell Culture and Membrane Preparation

CHO cells stably transfected with human adenosine AI receptor were grownand maintained in Dulbecco's Modified Eagles Medium with nutrientmixture F12 (DMEM/F12) without nucleosides, containing 10% fetal calfserum, penicillin (100 U/mL), streptomycin (100 μg/mL), L-glutamine (2mM) and Geneticin (G418, 0.2 mg/mL; A_(2B), 0.5 mg/mL) at 37° C. in 5%CO₂/95% air. Cells were then split 2 or 3 times weekly at a ratio ofbetween 1:5 and 1:20.

Membranes for radioligand binding experiments were prepared from freshor frozen cells as described in Klotz et al., Naunyn-Schmiedeberg'sArch. Pharmacol., 357:1-9 (1998). The cell suspension was thenhomogenized in ice-cold hypotonic buffer (5 mM Tris/HCl, 2 mM EDTA, pH7.4) and the homogenate was spun for 10 minutes (4° C.) at 1,000 g. Themembranes were then sedimented from the supernatant for 30 minutes at100,000 g and resuspended in 50 mM Tris/HCl buffer pH 7.4 (for A₃adenosine receptors: 50 mM Tris/HCl, 10 mM MgCl₂, 1 mM EDTA, pH 8.25),frozen in liquid nitrogen at a protein concentration of 1-3 mg/mL andstored at −80° C.

6.10 Example 10 Adenosine Receptor Binding Studies

The affinities of selected Purine Derivatives for the adenosine A₁receptor were determined by measuring the displacement of specific [³H]2-chloro-N⁶-cyclopentyl adenosine binding in CHO cells stablytransfected with human recombinant A₁ adenosine receptor expressed as Ki(nM).

Dissociation constants of unlabeled compounds (K_(i)-values) weredetermined in competition experiments in 96-well microplates using theA₁ selective agonist 2-chloro-N⁶-[³H]cyclopentyladenosine ([³H]CCPA, 1nM) for the characterization of A₁ receptor binding. Nonspecific bindingwas determined in the presence of 100 μM R-PIA and 1 mM theophylline,respectively. For details see Klotz et al., Naunyn-Schmiedeberg's Arch.Pharmacol., 357:1-9, 1998. All binding data were calculated bynon-linear curve fitting using the program SCTFIT (De Lean et al. Mol.Pharm. 1982, 21:5-16).

Results are presented in Table 1 below and show that Compounds 16, 17,18, 19, 23 (sodium salt), and 25, illustrative Purine Derivatives, areselective for the adenosine A₁ receptor and accordingly, are useful fortreating a Condition, slowing an animal's metabolic rate, or protectingan animal's heart against myocardial damage during cardioplegia.

TABLE 1 Affinities of illustrative Purine Derivatives for human A₁,A_(2A) and A₃ adenosine receptors Compound Ki(A₁)^(a) (nM)Ki(A_(2A))^(b) (nM) Ki(A₃)^(c) (nM) CCPA 0.83 2,270   42.3 (0.55-1.25)(1,950-2,660) (32.1-55.8) 16 2.63 4,190 513 (2.04-3.38) (2,440-7,200)(367-715) 17 0.97 4,692 704 (0.80-1.17) (2,300-9,560)   (400-1,240) 185.79   951 216 (4.73-7.10)   (530-1,708) (132-350) 19 7   10,000  900(5.14-9.23)  (5,790-15,760)   (445-1,890) 23 4.05 9,113 1,020   (sodiumsalt) (3.54-4.63)  (5,510-15,100)   (470-2,220) 25 10.6  >100,000   2020   (6.77-16.70)  (837-4870) ^(a)Displacement of specific [³H]CCPAbinding in CHO cells stably transfected with human recombinant A₁adenosine receptor, expressed as Ki (nM). ^(b)Displacement of specific[³H]NECA binding in CHO cells stably transfected with human recombinantA_(2A) adenosine receptor, expressed as Ki (nM). ^(c)Displacement ofspecific [³H]NECA binding in HEK cells stably transfected with humanrecombinant A₃ adenosine receptor, expressed as Ki (nM). All data aregeometric means with 95% confidence intervals in parantheses.

6.11 Example 11 Effects of Compound 17 on Septic Shock

Male BALB/c mice (6-8 weeks of age) were used in studies investigatinglipopolysaccharide-induced cytokine production and survival. Forcytokine production the mice were treated with compound 17 (Oraladministration of 0.03 mg/kg) orally by gavage 30 min before beingsubjected to lipopolysaccharide (1 mg/kg i.p.) for 90 minutes, afterthis period blood was taken and serum obtained for analysis. Serum wasdiluted 1:5 prior to being assayed for cytokines using species-specificELISA kits (R & D Systems) for the chemokine MIP-1α and the cytokineTNF-α levels, which were expressed as pg/mL. For survival studies micewere treated with compound 17 (Oral administration of 0.03 mg/kg)starting 30 mins prior to the mice being subjected to lipopolysaccharide(55 mg/kg i.p.). The survival of the mice was followed over 72 h andexpressed as a percentage of surviving mice at each time point. Oraladministration of 0.03 mg/kg compound 17 delays lipopolysaccharide (60mg/kg) induced mortality in conscious mice. N=12-14 per group.

FIG. 1 shows that Compound 17, administered orally to BALB/c mice at adose of 0.03 mg/kg, reduces lipopolysaccharide-induced plasma TNF-α andMIP-1α production in the BALB/c mouse model.

FIG. 2 shows that Compound 17, administered orally to BALB/c mice at adose of 0.03 mg/kg, reduces lipopolysaccharide-induced mortality in theBALB/c mouse model.

The above example shows that Compound 17, an illustrative PurineDerivative, reduces lipopolysaccharide-induced plasma levels of TNF-αand MIP-1α, and delays lipopolysaccharide-induced mortality in mice.

Accordingly, Compound 17 is useful for treating septic shock.

6.12 Example 12 Anti-Arrhythmia Effects of Compound 17

Heart Perfusion

Male Sprague-Dawley rats (having a body weight of 250 to 300 g) wereheparinized using sodium heparin (1,000 U/kg i.p.), followed 10 minuteslater by introduction of anesthesia via intraperitoneal administrationof sodium pentobarbital (40 mg/kg). Once the animal was anesthetized,the thorax was opened, and the heart was rapidly removed and perfusedthrough the ascending aorta using Krebs-Ringer buffer consisting of NaCl(118 mmol/liter), KCl (4.75 mmol/liter), KH₂PO₄ (1.18 mmol/liter), MgSO₄(1.18 mmol/liter), CaCl₂ (2.5 mmol/liter), NaHCO₃ (25 mmol/liter), andglucose (11 mmol/liter). A mixture of 95% O₂ and 5% CO₂ at 37° C. wasbubbled through the perfusate. The heart was initially perfused at aconstant pressure of 70 mm Hg. About 10 min after the constant pressureperfusion, perfusion was switched to constant flow perfusion achievedusing a microtube pump. The perfusion pressure was maintained at thesame level of constant pressure perfusion by adjusting flow rate. Oncethe flow rate was determined, it was maintained throughout theexperiment. The hearts were stimulated by rectangular pulses at a rateof 5 Hz and 2-millisecond duration and twice the diastolic threshold,delivered from a stimulus isolation unit (ADInstruments Ltd, Australia).

Effect of Compound 17 on Ischemia-Induced Arrhythmias

Rat hearts were perfused at constant pressure of 70 mmHg without pacingas described above. Bipolar epicardial electrocardiogram (ECG) wasrecorded by placing two electrodes on the surface of right appendage andapex. A stainless steel cannula was used as indifferent electrode. TheECG and heart rate were continuously monitored and data were recordedusing a PowerLab data acquisition system (ADInstruments Ltd, Australia)in conjunction with a Macintosh computer, and analyzed using Chart.3computer package. After a 20-minute equilibration period, regionalischemia was induced by ligation of the left anterior descending (LAD)coronary artery, and the ligature was released 30 minutes afterocclusion. Compound 17 was applied interperfusate 10 minutes before LADligation and was present during LAD ligation. Compound 17 was tested inthis model at 10, 30 and 100 pM concentrations. The incidences ofventricular tachycardia (VT) were almost same in control non-treated(12/12) and in treated hearts (20/22). Incidence of ventricularfibrillation (VF) was 58% (7/12) in non-treated hearts, and 9% (2/22) intreated hearts. The total duration of both VT and VF were significantlyshortened by compound 17 at concentrations of 30 and 100 pM.

FIG. 3 shows that Compound 17 reduces the duration of ischemia-inducedarrhythmias in isolated perfused rat hearts relative to a non-treatedcontrol group.

The above example shows that Compound 17, an illustrative PurineDerivative, reduces the incidence of ventricular fibrillation andaccordingly, is useful for treating a cardiac arrhythmia.

6.13 Example 13 Effect of Compound 17 on Function Recovery after GlobalIschemia/Reperfusion

Effect of Compound 17 on Function Recovery after Ischemia/Reperfusion

Rat hearts were initially perfused at a constant pressure of 70 mm Hgusing the procedure described above in section 6.12.1. After a 20minutes stabilization period, hearts were subjected to 30 minute no-flowischemia followed by 40 minute reperfusion. In treated hearts, Compound17 was infused for 10 minutes prior to induction of ischemia. Compound17 significantly improved +dp/dt_(max) after 30 minutes ischemiafollowed by 40 minutes of reperfusion at the concentration of 1 nM.Thus, the A1 agonist compound was not only effective in reducingfibrillations but was also effective in improving myocardialcontractility (dp/dt) in a myocardial ischemia-reperfusion model in theperfused heart. This observation is in line with data indicating thecardioprotective effect of A1 agonism in various models of ischemia andreperfusion (e.g. Roscoe et al., 2000; Jacobson et al., 2000; Lee etal., 2003), and the cardioprotective effect of A1 agonists in vitro(Goldenberg et al., 2003) and in vivo (Baxter et al., 2001; Donato etal., 2003; Kopecky et al., 2003; Kehl et al., 2003; Arora et al., 2003;Regan et al., 2003; Yang et al., 2003). Effect of compound 12 (1 nM) onmaximal rates of development of left ventricular pressure (+dP/dt_(max))after 30 minutes of ischemia followed by 40 minutes of reperfusion.*P<0.05 when compared with the value of control.

FIG. 4 shows that Compound 17 is useful in exerting a cardioprotectiveeffect following ischemia and reperfusion.

The above example shows that Compound 17, an illustrative PurineDerivative, is effective for reducing fibrillations and improvingmyocardial contractility following ischemia and reperfusion, andaccordingly, is useful in treating an ischemic condition or areperfusion injury.

6.14 Example 14 Synthesis of Compound 25

2′,3′-Isopropylidene-N⁶—(R)-(3-tetrahydrofuranyl) adenosine:2′,3′-isopropylidene-6-chloroadenosine (0.750 gm, 0.0023 mol) wasdiluted with ethanol (20 mL) and to the resultant solution was addedR-(3-aminotetrahydrofuranylamine•MeSO₃H (0.630 gm, 0.0035 mol), followedby triethylamine (0.9 mL). The resultant reaction was heated at refluxedfor 2 days, then cooled to room temperature and the resultant reactionmixture was concentrated in vacuo, diluted with water (25 mL) and ethylacetate (25 mL), and transferred to a separatory funnel. The organiclayer was separated, dried over sodium sulfate and concentrated in vacuoto provide a crude residue which was recrystallized from EtOAc-hexane toprovide 2′,3′-Isopropylidene-N⁶—(R)-(3-tetrahydrofuranyl) adenosine(0.680 gm).

N⁶—(R)-(3-Tetrahydrofuranyl) adenosine: Acetic anhydride (4.6 mL, 30eq.) was slowly added over a period of about 20 minutes to a stirringsolution of nitric acid (0.8 mL, 63% purchased from ACROS) which hadbeen precooled to about −5° C. using an acetonitrile-CO₂ bath. Theinitial reaction is vigorous and addition should be done very carefullyto avoid the increase in temperature. After addition of acetic anhydrideis complete, the resultant solution was cooled to −20° C. and2′,3′-isopropylidene-N⁶—R-(3-tetrahydrofuranyl)-adenosine (0.605, 0.0016mol) was added. The resultant reaction was monitored using thin-layerchromatography (solvent 5% MeOH—CH₂Cl₂ or 70% EtOAc-hexane). When thereaction was complete, the reaction mixture was poured slowly into acold solution of NaHCO₃ (100 mL) and the resultant solution was dilutedwith ethyl acetate (100 mL), allowed to stir for 5 minutes, thentransferred to a separatory funnel. The organic layer was collected andthe aqueous layer was extracted with ethyl acetate (50 mL). The combinedorganic layers were then washed with water, dried over sodium sulfate,and concentrated in vacuo to afford a crude residue. The crude residuewas diluted with TFA (16 mL) and water (4 mL) and the resultant solutionwas allowed to stir at room temperature for 30 minutes, thenconcentrated in vacuo. The resultant residue was diluted with water andconcentrated in vivo to afford a crude product which was purified usingflash column chromatograpy on silica gel using 10%methanol-dichloromethane to provide Compound 25 (265 mg). ¹H-NMR(DMSO-d₆): δ 1.97-2.10 (m, 1H), 2.12-2.20 (m, 1H), 3.57-3.61 (dd, J=4.8and 4.5 Hz, 1H), 3.67-3.74 (dd, J=8.1 and 8.1 Hz, 1H), 3.81-3.92 (m,2H), 4.12-4.17 (m, 1H), 4.30 (s, 1H), 4.67 9s, 1H), 4.74-4.87 (m, 3H),5.48 9s, 1H), 5.61 (s, 1H), 5.91 (d, J=5.1 Hz, 1H), 7.99 (d, J=4.8 Hz,1H), 8.20 (s, 1H), 8.34 (s, 1H); MS (ES⁺): m/z 383.06 (M+1).

6.15 Example 15 Effect of Compound 17 on Pain

Male mice (body weight of 25-35 grams) were put in groups as follows: afirst group which was intreperitoneally administered buprenorphine (0.3mg/kg), a second group which was intreperitoneally administeredbuprenorphine (1 mg/kg), a third group which was intreperitoneallyadministered Compound 17 (3 mg/kg), a fourth group which wasintreperitoneally co-administered Compound 17 (3 mg/kg) andbuprenorphine (1.0 mg/kg), and a fifth group which was intreperitoneallyco-administered Compound 17 (3 mg/kg) and buprenorphine (0.3 mg/kg). Theanalgesic effects in mice was measured using an IITC model 33 tail-flickanalgesia meter (IITC Inc., Woodland Hills, Calif.) at 0 minutes(baseline control), 5 minutes, 15 minutes, 30 minutes and 60 minutes (insome cases also 90 and 120 minutes) post-treatment, compound or vehicletreatment. Average recoding value of two readings was used for each timepoint. A baseline for every mouse between 2-4 seconds of latency and a10-second cut-off time was set for the maximum possible effect ofanalgesia (% MPE). % MPE was calculated using the following formula: %MPE=[(post-drug value−baseline)/(cut-off time−baseline)]×100.

FIG. 5 shows that Compound 17 is useful in exerting an analgesic effectin an animal.

The results show that Compound 17, an illustrative Purine Derivative,exerts a analgesic effect in an animal, and, accordingly, is useful forthe treatment of pain.

6.16 Example 16 Effect of Compound 17 on Pain

Male mice (each having a body weight of 20-30 g) were subcutaneouslyadministered 20 μl of a 1% formalin solution in formaldehyde (preparedby diluting a commercial 4% [w/v] stock formalin solution) into thedorsal region of their left hind paw. The mice were assigned to either acontrol group and administered vehicle, or to a treatment group andintraperitoneally administered Compound 17 (1.0 mg/kg). Both groups ofanimals were monitored for a reaction for 30 minutes post-treatment todetermine how much time each animal spends licking the treated paw. Thelicking time in control group (vehicle pretreated animals) was thencompared to the licking time in the treatment group in order tocalculate the analgesic effect. The 30 minute reaction period wasdivided into two phases: an early phase which lasts from 0-5 minutespost-treatment, and a late phase which lasts from 10-30 minutespost-treatment.

FIG. 6 shows that Compound 17 is useful in exerting an analgesic effectin an animal.

The results indicate that Compound 17, an illustrative PurineDerivative, exhibits an analgesic effect during the late phase of theresponse and, accordingly, is useful for treating pain.

6.17 Example 17 Effect of Compound 17 on Pain

BALB/C mice (6-8 weeks of age) were intraperitoneally administeredstreptozotocin (40 mg/kg, once per day for 5 consecutive days) to inducediabetes (blood glucose levels were greater than 200 mg/mL). Three weeksafter the first streptozotocin injection, the animals wereintraperitoneally administered Compound 17 (1 mg/kg) into a rear paw andpost-treatment allodynia was measured using an Electrovonfreyanesthesiometer (IITC Inc., Woodland Hills Calif. 91367). The analgesicactivity of Compound 17 was measured at 0 minutes (control), 15 minutes,30 minutes and 60 minutes time point after administration of Compound17.

FIG. 7 shows that Compound 17 is useful in exerting an analgesic effectin a animal.

The results indicate that Compound 17, an illustrative PurineDerivative, produces a marked and lasting analgesic effect, and,accordingly, is useful for treating pain in an animal.

6.18 Example 18 Effect of Compound 17 on Pain

Male Wistar rats (each weighing between 200-250 g, kept underpathogen-free conditions at 24-25° C. and provided with standard ratchow and water ad libitum) were anaesthetized via intraperitonealadministration of pentobarbital (50 mg/kg) and placed in a stereotaxicframe. The atlanto-occipital membrane was exposed and a PE-10 catheter(7.5 cm) was inserted through an incision into the subarachnoidal space.The external end of the catheter was then fixed to the skull, the woundwas closed, and the rats were allowed to recover for 7 dayspost-surgery. Animals without neurological deficits were placed in aplexiglass observation chamber on a metal mesh surface and mechanicalthresholds of the plantar surface of the paw were determined using aDynamic Plantar Aesthesiometer (Ugo Basile, Italy) as follows: Followingacclimation, the touch stimulator unit was placed under the animal's pawsuch that the filament was positioned under the target area of the paw.The filament was then lifted such that it contacted the pad of theanimal's paw and continually exerted an increasing upward force on thepaw until the animal withdrew the paw. The paw withdrawal threshold wasmeasured 5 times in this manner in turns and the mean of the 5 valueswas calculated. After control threshold measurements were complete,carrageenan (3%, 100 μl) was administered subcutaneously into a hindpaw,resulting in marked swelling and redness of the treated paw. Three hoursafter the carrageenan administration, the threshold values were measuredagain. The animals were then divided into a control group (administeredvehicle intrathecally) and a treatment group (adminstered Compound 17intrathecally at in a 10 μl injection volume). Threshold determinationswere repeated as describe above at 15 minutes, 30 minutes, 60 minutes,90 minutes and 120 minutes after the administration of vehicle orCompound 17.

FIG. 8 shows that Compound 17 exerts an analgesic effect in a animal.

Results show that Compound 17, an illustrative Purine Derivative, iseffective for raising the pain threshold in a rat model of pain, and,accordingly, is useful for treating pain.

6.19 Example 19 Effect of Compound 17 on Pain

Male CD rats (each weighing from 220 g to 250 g) were prepared accordingto the procedure set forth in Z. Seltzer et al., Pain, 43:205-218(1990). The rats were then anesthetized via intraperitonealadministration of sodium pentobarbital (50 mg/kg). A skin incision wasmade at the upper ⅓ and ⅔ left thigh area of each rat and the leftsciatic nerve was exposed and freed from the surrounding connectivetissue. An 8-0 nylon suture was then used to tightly ligate the leftsciatic nerve of each rat so that the dorsal ⅓ to ½ of the nervethickness was trapped in the ligature. The incision was closed using 4-0sterile suture. Seven days post-surgery, the animals were put into fourgroups: a first group that was administered vehicle (control group); asecond group that was administered Compound 17 at 0.1 mg/kg; a thirdgroup that was administered buprenorphine at 0.3 mg/kg; and a fourthgroup that was co-administered Compound 17 at 0.1 mg/kg andbuprenorphine at 0.3 mg/kg. Animals in all four groups were assessed forallodynia immediately prior to treatment and at 10, 20, 30 and 60minutes post-treatment using the Von Frey Hair test (G. M. Pitcher etal., J Neurosci Methods, 87:185-93 (1999)).

FIG. 9 shows that Compound 17, alone or in combination withbuprenorphine, exerts an analgesic effect in a animal.

The results show that Compound 17, an illustrative Purine Derivative,exerts an analgesic effect in an animal, and, accordingly, is useful fortreating pain.

6.20 Example 20 Effect of Compound 17 on Heart Rate

Adult male Wistar rats (each weighing from about 350 g to about 400 g)were anesthetized as in Example 19, then prepared for monitoring ofblood pressure and heart rate. Compound 17 was then intravenouslyadministered via the femoral vein at a dose of 1 ng/kg/minute, 10ng/kg/minute, or 1000 ng/kg/minute (n=2 animals per dosage size) for atotal administration period of 20 minutes.

The results show that a 10 ng/kg/minute dose of lowered heart rate from440 beats per minute to 370 beats per minute and that the 1000ng/kg/minute dose reduced heart rate from 440 beats per minute to 150beats per minute. Thus, Compound 17, an illustrative Purine Derivativeis exerts a heart rate lowering effect, and accordingly, a PurineDerivative is useful for lowering an animal's ventricular rate to a rateof not less than about 40 beats per minute.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

All references cited herein are incorporated by reference in theirentirety.

1. A method for treating a neurological disorder, a cardiovasculardisease, an ischemic condition, diabetes, obesity, a wasting disease ora reperfusion injury, or a neurological disorder selected from the groupconsisting of pain, headache, a sleep disorder, a cranial nervedisorder, a neuromuscular disease, a cerebrovascular disease and aneuroopthalmic disorder, the method comprising administering to ananimal in need thereof a compound of: 1) formula (Ia):

wherein A is —CH₂OSO₂NH₂; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —C₃-C₈ monocyclic cycloalkyl, —C₃-C₈ monocycliccycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —C₈-C₁₂ bicyclic cycloalkyl,or —C₈-C₁₂ bicyclic cycloalkenyl; R² is -halo, —CN, —NHR⁸, —OR⁸, —SR⁸,—NHC(O)OR⁸, —NHC(O)R⁴, —NHC(O)NHR⁸, —NHNHC(O)R⁴, —NHNHC(O)OR⁸,—NHNHC(O)NHR⁸, or —NH—N═C(R⁶)R⁷; R⁴ is —H, —C₁-C₁₅ alkyl, -aryl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle),—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl; R⁶ is —C₁-C₁₀ alkyl,-aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-(3-to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), -phenylene-(CH₂)_(n)COOH, or-phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl); R⁷ is —H, —C₁-C₁₀ alkyl, -aryl,—(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-(3-to 7-membered monocyclic heterocycle), or —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle); R₈ is —C₁-C₁₅ alkyl, -aryl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl; and each n isindependently an integer ranging from 1 to 5; 2) formula (Ib):

wherein A is —CH₂ONO₂; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —C₁-C₁₀ alkyl, -aryl, -3- to 7-membered monocyclicheterocycle, -8- to 12-membered bicyclic heterocycle, —C₃-C₈ monocycliccycloalkyl, —C₃-C₈ monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl,—C₈-C₁₂ bicyclic cycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl; R² is —CN, —NHR⁴, —NHC(O)R⁴, —NHC(O)OR⁴, —NHC(O)NHR⁴,—NHNHC(O)R⁴, —NHNHC(O)OR⁴, —NHNHC(O)NHR⁴, or —NH—N═C(R⁶)R⁷; R⁴ is—C₁-C₁₅ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to 7-memberedmonocyclic heterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclicheterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —C≡C—(C₁-C₁₀alkyl) or —C≡C-aryl; R⁶ is —C₁-C₁₀ alkyl, -aryl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),-phenylene-(CH₂)_(n)COOH, or -phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl); R⁷is —H, —C₁-C₁₀ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl) or —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl); and each n isindependently an integer ranging from 1 to 5; 3) formula (Ic):

wherein A is —CH₂NHR⁵; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —H, —C₁-C₁₀ alkyl, -aryl, -3- to 7-membered monocyclicheterocycle, -8- to 12-membered bicyclic heterocycle, —C₃-C₈ monocycliccycloalkyl, —C₃-C₈ monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl,—C₈-C₁₂ bicyclic cycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl; R² is —NHR⁴, —OR⁴, —SR⁴, —NHC(O)R⁴, —NHC(O)OR⁴,—NHC(O)NHR⁴, —NHNHC(O)R⁴, —NHNHC(O)NHR⁴, or —NHNHC(O)OR⁴; R⁴ is —C₁-C₁₅alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to 7-membered monocyclicheterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —C≡C—(C₁-C₁₀ alkyl) or—C≡C-aryl; R⁵ is —C(O)O(C₁-C₁₀ alkyl), —C(O)NH(C₁-C₁₀ alkyl),—C(O)N(C₁-C₁₀ alkyl)₂, —C(O)NH-aryl, —CH(NH₂)NH₂ or —CH(NH₂)NH(C₁-C₁₀alkyl); and each n is independently an integer ranging from 1 to 5; 4)formula (Id):

wherein A is —R³; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —C₁-C₁₀ alkyl, -aryl, -3- to 7-membered monocyclicheterocycle, -8- to 12-membered bicyclic heterocycle, —C₃-C₈ monocycliccycloalkyl, —C₃-C₈ monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl,—C₈-C₁₂ bicyclic cycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl; R² is —H, -halo, —CN, —NHR⁴, —OR⁴, —SR⁴, —NHC(O)R⁴,—NHC(O)OR⁴, —NHC(O)NHR⁴, —NHNHC(O)R⁴, —NHNHC(O)NHR⁴, —NHNHC(O)OR⁴ or—NH—N═C(R⁶)R⁷; R³ is —CH₂ONO or —CH₂OSO₃H; R⁴ is —C₁-C₁₅ alkyl, -aryl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle),—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl; R⁶ is —C₁-C₁₀ alkyl,-aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-(3-to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), -phenylene-(CH₂)_(n)COOH, or-phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl); R⁷ is —H, —C₁-C₁₀ alkyl, -aryl,—(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-(3-to 7-membered monocyclic heterocycle), or —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle); and each n is independently an integer rangingfrom 1 to 5; 5) formula (Ie):

wherein A is —CH₂R³; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is -3- to 7-membered monocyclic heterocycle, -8- to12-membered bicyclic heterocycle, —C₃-C₈ monocyclic cycloalkyl, —C₃-C₈monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl, —C₈-C₁₂ bicycliccycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl; R² is -halo, —CN, —NHC(O)R⁴, —NHR⁴, —OR⁴, —SR⁴,—NHC(O)OR⁴, —NHC(O)NHR⁴, —NHNHC(O)R⁴, —NHNHC(O)OR⁴, —NHNHC(O)NHR⁴, or—NH—N═C(R⁶)R⁷; R³ is —OSO₂NH(C₁-C₁₀ alkyl), —OSO₂N(C₁-C₁₀ alkyl)₂, or—OSO₂NH-aryl; R⁴ is —C₁-C₁₅ alkyl, -aryl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl; R⁶ is —C₁-C₁₀ alkyl,-aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-(3-to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), -phenylene-(CH₂)_(n)COOH, or-phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl); R₇ is —H, —C₁-C₁₀ alkyl, -aryl,—(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle), or—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle); and each n isindependently an integer ranging from 1 to 5; 6) formula (If):

wherein A is —CH₂ONO₂; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —C₃-C₈ monocyclic cycloalkyl; and R² is —H or -halo; 7)formula (Ig):

wherein A is —CH₂ONO₂; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; and R¹ is -aryl, -3- to 7-membered monocyclic heterocycle, -8- to12-membered bicyclic heterocycle, —C₃-C₈ monocyclic cycloalkyl, —C₃-C₈monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl, —C₈-C₁₂ bicycliccycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), R² is —H or -halo; or a pharmaceutically acceptable saltthereof in an amount effective to treat the neurological disorder, suchthat said neurological disorder, cardiovascular disease, ischemiccondition, diabetes, obesity, wasting disease or reperfusion injury istreated.
 2. A method for protecting an animal's heart against myocardialdamage during cardioplegia, the method comprising administering to ananimal in need thereof a cardioplegia-inducing agent and an effectiveamount of a compound of: 1) formula (Ia):

wherein A is —CH₂OSO₂NH₂; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —C₃-C₈ monocyclic cycloalkyl, —C₃-C₈ monocycliccycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —C₈-C₁₂ bicyclic cycloalkyl,or —C₈-C₁₂ bicyclic cycloalkenyl; R² is -halo, —CN, —NHR⁸, —OR⁸, —SR⁸,—NHC(O)OR⁸, —NHC(O)R⁴, —NHC(O)NHR⁸, —NHNHC(O)R⁴, —NHNHC(O)OR⁸,—NHNHC(O)NHR⁸, or —NH—N═C(R⁶)R⁷; R⁴ is —H, —C₁-C₁₅ alkyl, -aryl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle),—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl; R⁶ is —C₁-C₁₀ alkyl,-aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-(3-to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), -phenylene-(CH₂)—COOH, or-phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl); R⁷ is —H, —C₁-C₁₀ alkyl, -aryl,—(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl), —(CH₂),—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-(3-to 7-membered monocyclic heterocycle), or —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle); R₈ is —C₁-C₁₅ alkyl, -aryl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to12-membered bicyclic heterocycle), —(CH₂), —(C₃-C₈ monocycliccycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl; and each n isindependently an integer ranging from 1 to 5; 2) formula (Ib):

wherein A is —CH₂ONO₂; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —C₁-C₁₀ alkyl, -aryl, -3- to 7-membered monocyclicheterocycle, -8- to 12-membered bicyclic heterocycle, —C₃-C₈ monocycliccycloalkyl, —C₃-C₈ monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl,—C₈-C₁₂ bicyclic cycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂), —(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl; R² is —CN, —NHR⁴, —NHC(O)R⁴, —NHC(O)OR⁴, —NHC(O)NHR⁴,—NHNHC(O)R⁴, —NHNHC(O)OR⁴, —NHNHC(O)NHR⁴, or —NH—N═C(R⁶)R⁷; R⁴ is—C₁-C₁₅ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to 7-memberedmonocyclic heterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclicheterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl), —(CH₂), —(C₃-C₈monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —C≡C—(C₁-C₁₀ alkyl) or—C≡C-aryl; R⁶ is —C₁-C₁₀ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3-to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl), —(CH₂),—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂), —(C₃-C₈monocyclic cycloalkenyl), -phenylene-(CH₂)_(n)COOH, or-phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl); R⁷ is —H, —C₁-C₁₀ alkyl, -aryl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle),—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl) or —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl); and each n is independently an integer ranging from 1 to 5;3) formula (Ic):

wherein A is —CH₂NHR⁵; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —H, —C₁-C₁₀ alkyl, -aryl, -3- to 7-membered monocyclicheterocycle, -8- to 12-membered bicyclic heterocycle, —C₃-C₈ monocycliccycloalkyl, —C₃-C₈ monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl,—C₈-C₁₂ bicyclic cycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl; R² is —NHR⁴, —OR⁴, —SR⁴, —NHC(O)R⁴, —NHC(O)OR⁴,—NHC(O)NHR⁴, —NHNHC(O)R⁴, —NHNHC(O)NHR⁴, or —NHNHC(O)OR⁴; R⁴ is —C₁-C₁₅alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to 7-membered monocyclicheterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —C≡C—(C₁-C₁₀ alkyl) or—C≡C-aryl; R⁵ is —C(O)O(C₁-C₁₀ alkyl), —C(O)NH(C₁-C₁₀ alkyl),—C(O)N(C₁-C₁₀ alkyl)₂, —C(O)NH-aryl, —CH(NH₂)NH₂ or —CH(NH₂)NH(C₁-C₁₀alkyl); and each n is independently an integer ranging from 1 to 5; 4)formula (Id):

wherein A is —R³; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —C₁-C₁₀ alkyl, -aryl, -3- to 7-membered monocyclicheterocycle, -8- to 12-membered bicyclic heterocycle, —C₃-C₈ monocycliccycloalkyl, —C₃-C₈ monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl,—C₈-C₁₂ bicyclic cycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl; R² is —H, -halo, —CN, —NHR⁴, —OR⁴, —SR⁴, —NHC(O)R⁴,—NHC(O)OR⁴, —NHC(O)NHR⁴, —NHNHC(O)R⁴, —NHNHC(O)NHR⁴, —NHNHC(O)OR⁴ or—NH—N═C(R⁶)R⁷; R³ is —CH₂ONO or —CH₂OSO₃H; R⁴ is —C₁-C₁₅ alkyl, -aryl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle),—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl; R⁶ is —C₁-C₁₀ alkyl,-aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-(3-to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), -phenylene-(CH₂)_(n)COOH, or-phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl); R⁷ is —H, —C₁-C₁₀ alkyl, -aryl,—(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-(3-to 7-membered monocyclic heterocycle), or —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle); and each n is independently an integer rangingfrom 1 to 5; 5) formula (Ie):

wherein A is —CH₂R³; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is -3- to 7-membered monocyclic heterocycle, -8- to12-membered bicyclic heterocycle, —C₃-C₈ monocyclic cycloalkyl, —C₃-C₈monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl, —C₈-C₁₂ bicycliccycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl; R² is -halo, —CN, —NHC(O)R⁴, —NHR⁴, —OR⁴, —SR⁴,—NHC(O)OR⁴, —NHC(O)NHR⁴, —NHNHC(O)R⁴, —NHNHC(O)OR⁴, —NHNHC(O)NHR⁴, or—NH—N═C(R⁶)R⁷; R³ is —OSO₂NH(C₁-C₁₀ alkyl), —OSO₂N(C₁-C₁₀ alkyl)₂, or—OSO₂NH-aryl; R⁴ is —C₁-C₁₅ alkyl, -aryl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl; R⁶ is —C₁-C₁₀ alkyl,-aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-(3-to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), -phenylene-(CH₂)_(n)COOH, or-phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl); R₇ is —H, —C₁-C₁₀ alkyl, -aryl,—(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle), or—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle); and each n isindependently an integer ranging from 1 to 5; 6) formula (If):

wherein A is —CH₂ONO₂; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —C₁-C₈ monocyclic cycloalkyl; and R² is —H or -halo; 7)formula (Ig):

wherein A is —CH₂ONO₂; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; and R¹ is —C₁-C₁₀ alkyl, -aryl, -3- to 7-membered monocyclicheterocycle, -8- to 12-membered bicyclic heterocycle, —C₃-C₈ monocycliccycloalkyl, —C₃-C₈ monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl,—C₈-C₁₂ bicyclic cycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), R² is —H or -halo; 8) formula (II):

wherein A is —CH₂OH; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; each R¹ is independently —H, —C₁-C₁₀ alkyl, —(CH₂)_(m)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(m)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(m)—(C₈-C₁₂ bicyclic cycloalkyl),—(CH₂)_(m)—(C₈-C₁₂ bicyclic cycloalkenyl), or —(CH₂)_(m)-aryl, or bothR¹ groups together with the carbon atom to which they are attached forma —C₃-C₈ monocyclic cycloalkyl, a —C₃-C₈ monocyclic cycloalkenyl, a—C₈-C₁₂ bicyclic cycloalkyl, or a —C₈-C₁₂ bicyclic cycloalkenyl; R² is—OR⁴, —SR⁴, —NHNHC(O)R³, —NHNHC(O)NHR³, —NHNHC(O)OR⁷, or —NH—N═C(R⁵)R⁶;R³ is —H, —C¹-C¹⁰ alkyl, —(CH²)_(n)-(3- to 7-membered monocyclicheterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-aryl,—O—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —O—(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), O—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl; R⁴ is —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)-aryl, or —C≡C-aryl; R⁵ and R⁶ are eachindependently —H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to 7-membered monocyclicheterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-aryl,-phenylene-(CH₂)_(n)COOH, or -phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl), orR⁵ and R⁶ together with the carbon atom to which they are attached forma C₃-C₈ monocyclic cycloalkyl or a C₈-C₁₂ bicyclic cycloalkyl; R⁷ is —H,—C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle),—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —(CH₂)_(n)-aryl, —C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl; m isan integer ranging from 0 to 3; and each n is independently an integerranging from 0 to 5; 9) formula (III):

wherein A is —CH₂R³; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; each R¹ is independently —C₁-C₁₀ alkyl, —(CH₂)_(m)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(m)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(m)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(m)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(m)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(m)-aryl, or two R¹ groups, together with the carbon atom towhich they are attached, form a —C₃-C₈ monocyclic cycloalkyl, a —C₃-C₈monocyclic cycloalkenyl, a —C₈-C₁₂ bicyclic cycloalkyl, or a —C₈-C₁₂bicyclic cycloalkenyl; R² is —H, —CN, -halo, —N(R⁴)², —OR⁴, —SR⁴,—NHC(O)R⁴, —NHC(O)OR⁴, —NHC(O)NHR⁴, —NHNHC(O)R⁴, —NHNHC(O)NHR⁴,—NHNHC(O)OR⁴, or —NH—N═C(R⁶)R⁷; R³ is —ONO², —ONO, —OSO₃H, —OSO₂NH₂,—OSO₂NH(C₁-C₁₀ alkyl), —OSO₂N(C₁-C₁₀ alkyl)₂, —OSO₂NH-aryl or —N(R⁵)₂;each R⁴ is independently —H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to 7-memberedmonocyclic heterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclicheterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-aryl,—C(O)O(C₁-C₁₀ alkyl), —C(O)NH(C₁-C₁₀ alkyl), —C(O)N(C₁-C₁₀ alkyl)₂,—C(O)NH-aryl, —C(O)N(C₁-C₁₀ alkyl)₂, —CH(NH₂)NH₂ or —CH(NH₂)NH(C₁-C₁₀alkyl); each R⁵ is independently —H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl, —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl; R⁶ and R⁷ are each independently —H, —C₁-C₁₀ alkyl,—(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —(CH₂)_(n)-aryl, -phenylene-(CH₂)_(n)COOH, or-phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl), or R⁶ and R⁷, together with thecarbon atom to which they are attached, form a —C₃-C₈ monocycliccycloalkyl, —C₃-C₈ monocyclic cycloalkenyl, or a C₈-C₁₂ bicycliccycloalkenyl; m is an integer ranging from 0 to 3; and each n isindependently an integer ranging from 0 to 5; 10) formula (IV):

wherein A is —CH₂OH; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —C₃-C₈ monocyclic cycloalkyl or —C₃-C₈ monocycliccycloalkenyl; R² is —H, -halo, —CN, —OR³, —SR³, —N(R³)₂, —NHNHC(O)R³,—NHNHC(O)NHR³, —NHNHC(O)OR³, or —NH—N═C(R⁴)R⁵; each R³ is independently—H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle),—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —(CH₂)_(n)-aryl, —C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl; R⁴ andR⁵ are each independently —H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-aryl,-phenylene-(CH₂)_(n)COOH, or -phenylene-(CH₂)_(n)COO(C₁-C₁₀ alkyl), orR⁴ and R⁵, together with the carbon atom to which they are attached,form a C₃-C₈ monocyclic cycloalkyl, a C₃-C₈ monocyclic cycloalkenyl, a—C₈-C₁₂ bicyclic cycloalkyl, or a —C₈-C₁₂ bicyclic cycloalkenyl; andeach n is independently an integer ranging from 0 to 5; 11) formula (V):

wherein A is —CH₂OH; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —C₁-C₁₀ alkyl, —(CH₂)_(m)-(3- to 7-membered monocyclicheterocycle), —(CH₂)_(m)-(8- to 12-membered bicyclic heterocycle),—(CH₂)_(m)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —(CH₂)_(m)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(m)—(C₃-C₈ monocyclic cycloalkenyl) or —(CH₂)_(m)-aryl, or R¹ andR^(1a) together with the carbon atom to which they are attached form a—C₃-C₈ monocyclic cycloalkyl, a —C₃-C₈ monocyclic cycloalkenyl, a—C₈-C₁₂ bicyclic cycloalkyl, or a —C₈-C₁₂ bicyclic cycloalkenyl; R^(1a)is —C₃-C₈ monocyclic cycloalkyl or —C₃-C₈ monocyclic cycloalkenyl; R² is—OR⁴, —SR⁴, —NHNHC(O)R³, —NHNHC(O)NHR³, —NHNHC(O)OR³, or —NH—N═C(R⁵)R⁶;R³ is —H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to 7-membered monocyclicheterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-aryl, —C≡C—(C₁-C₁₀alkyl) or —C≡C-aryl; R⁴ is —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to 7-memberedmonocyclic heterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclicheterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)-aryl, —C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl; R⁵ andR⁶ are each independently —H, —C₁-C₁₀ alkyl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-aryl,-phenylene-(CH₂)_(n)COOH, or -phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl), orR⁵ and R⁶ together with the carbon atom to which they are attached forma C₃-C₈ monocyclic cycloalkyl, a C₃-C₈ monocyclic cycloalkenyl, a—C₈-C₁₂ bicyclic cycloalkyl, or a —C₈-C₁₂ bicyclic cycloalkenyl; m is aninteger ranging from 0 to 3; and each n is independently an integerranging from 0 to 5; or pharmaceutically acceptable salt of the compoundof claim 1, such that said animal's heart is protected againstmyocardial damage during cardioplegia.
 3. A method for reducing ananimal's rate of metabolism or rate of oxygen consumption, the methodcomprising administering to an animal in need thereof a compound of: 1)formula (Ia):

wherein A is —CH₂OSO₂NH₂; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —C₃-C₈ monocyclic cycloalkyl, —C₃-C₈ monocycliccycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —C₈-C₁₂ bicyclic cycloalkyl,or —C₈-C₁₂ bicyclic cycloalkenyl; R² is -halo, —CN, —NHR⁸, —OR⁸, —SR⁸,—NHC(O)OR⁸, —NHC(O)R⁴, —NHC(O)NHR⁸, —NHNHC(O)R⁴, —NHNHC(O)OR⁸,—NHNHC(O)NHR⁸, or —NH—N═C(R⁶)R⁷; R⁴ is —H, —C₁-C₁₅ alkyl, -aryl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle),—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl; R⁶ is —C₁-C₁₀ alkyl,-aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-(3-to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), -phenylene-(CH₂)_(n)COOH, or-phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl); R⁷ is —H, —C₁-C₁₀ alkyl, -aryl,—(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-(3-to 7-membered monocyclic heterocycle), or —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle); R₈ is —C₁-C₁₅ alkyl, -aryl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl; and each n isindependently an integer ranging from 1 to 5; 2) formula (Ib):

wherein A is —CH₂ONO₂; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —C₁-C₁₀ alkyl, -aryl, -3- to 7-membered monocyclicheterocycle, -8- to 12-membered bicyclic heterocycle, —C₃-C₈ monocycliccycloalkyl, —C₃-C₈ monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl,—C₈-C₁₂ bicyclic cycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl; R² is —CN, —NHR⁴, —NHC(O)R⁴, —NHC(O)OR⁴, —NHC(O)NHR⁴,—NHNHC(O)R⁴, —NHNHC(O)OR⁴, —NHNHC(O)NHR⁴, or —NH—N═C(R⁶)R⁷; R⁴ is—C₁-C₁₅ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to 7-memberedmonocyclic heterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclicheterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —C≡C—(C₁-C₁₀alkyl) or —C≡C-aryl; R⁶ is —C₁-C₁₀ alkyl, -aryl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),-phenylene-(CH₂)_(n)COOH, or -phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl); R⁷is —H, —C₁-C₁₀ alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl) or —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl); and each n isindependently an integer ranging from 1 to 5; 3) formula (Ic):

wherein A is —CH₂NHR⁵; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —H, —C₁-C₁₀ alkyl, -aryl, -3- to 7-membered monocyclicheterocycle, -8- to 12-membered bicyclic heterocycle, —C₃-C₈ monocycliccycloalkyl, —C₃-C₈ monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl,—C₈-C₁₂ bicyclic cycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl; R² is —NHR⁴, —OR⁴, —SR⁴, —NHC(O)R⁴, —NHC(O)OR⁴,—NHC(O)NHR⁴, —NHNHC(O)R⁴, —NHNHC(O)NHR⁴, or —NHNHC(O)OR⁴; R⁴ is —C₁-C₁₅alkyl, -aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to 7-membered monocyclicheterocycle), —(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —C≡C—(C₁-C₁₀ alkyl) or—C≡C-aryl; R⁵ is —C(O)O(C₁-C₁₀ alkyl), —C(O)NH(C₁-C₁₀ alkyl),—C(O)N(C₁-C₁₀ alkyl)₂, —C(O)NH-aryl, —CH(NH₂)NH₂ or —CH(NH₂)NH(C₁-C₁₀alkyl); and each n is independently an integer ranging from 1 to 5; 4)formula (Id):

wherein A is —R³; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —C₁-C₁₀ alkyl, -aryl, -3- to 7-membered monocyclicheterocycle, -8- to 12-membered bicyclic heterocycle, —C₃-C₈ monocycliccycloalkyl, —C₃-C₈ monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl,—C₈-C₁₂ bicyclic cycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl; R² is —H, -halo, —CN, —NHR⁴, —OR⁴, —SR⁴, —NHC(O)R⁴,—NHC(O)OR⁴, —NHC(O)NHR⁴, —NHNHC(O)R⁴, —NHNHC(O)NHR⁴, —NHNHC(O)OR⁴ or—NH—N═C(R⁶)R⁷; R³ is —CH₂ONO or —CH₂OSO₃H; R⁴ is —C₁-C₁₅ alkyl, -aryl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle),—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈monocyclic cycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl; R⁶ is —C₁-C₁₀ alkyl,-aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-(3-to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), -phenylene-(CH₂)_(n)COOH, or-phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl); R⁷ is —H, —C₁-C₁₀ alkyl, -aryl,—(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-(3-to 7-membered monocyclic heterocycle), or —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle); and each n is independently an integer rangingfrom 1 to 5; 5) formula (Ie):

wherein A is —CH₂R³; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is -3- to 7-membered monocyclic heterocycle, -8- to12-membered bicyclic heterocycle, —C₃-C₈ monocyclic cycloalkyl, —C₃-C₈monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl, —C₈-C₁₂ bicycliccycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), or—(CH₂)_(n)-aryl; R² is -halo, —CN, —NHC(O)R⁴, —NHR⁴, —OR⁴, —SR⁴,—NHC(O)OR⁴, —NHC(O)NHR⁴, —NHNHC(O)R⁴, —NHNHC(O)OR⁴, —NHNHC(O)NHR⁴, or—NH—N═C(R⁶)R⁷; R³ is —OSO₂NH(C₁-C₁₀ alkyl), —OSO₂N(C₁-C₁₀ alkyl)₂, or—OSO₂NH-aryl; R⁴ is —C₁-C₁₅ alkyl, -aryl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to12-membered bicyclic heterocycle), —(CH₂)_(n)—(C₃-C₈ monocycliccycloalkyl), —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl),—(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkenyl), —C≡C—(C₁-C₁₀ alkyl) or —C≡C-aryl; R⁶ is —C₁-C₁₀ alkyl,-aryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkenyl), —(CH₂)_(n)-(3-to 7-membered monocyclic heterocycle), —(CH₂)_(n)-(8- to 12-memberedbicyclic heterocycle), -phenylene-(CH₂)_(n)COOH, or-phenylene-(CH₂)_(n)COO—(C₁-C₁₀ alkyl); R₇ is —H, —C₁-C₁₀ alkyl, -aryl,—(CH₂)_(n)-aryl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl),—(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicycliccycloalkyl), —(CH₂)_(n)-(3- to 7-membered monocyclic heterocycle), or—(CH₂)_(n)-(8- to 12-membered bicyclic heterocycle); and each n isindependently an integer ranging from 1 to 5; 6) formula (If):

wherein A is —CH₂ONO₂; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —C₃-C₈ monocyclic cycloalkyl; and R² is —H or -halo; 7)formula (Ig):

wherein A is —CH₂ONO₂; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; and R¹ is -aryl, -3- to 7-membered monocyclic heterocycle, -8- to12-membered bicyclic heterocycle, —C₃-C₈ monocyclic cycloalkyl, —C₃-C₈monocyclic cycloalkenyl, —C₈-C₁₂ bicyclic cycloalkyl, —C₈-C₁₂, bicycliccycloalkenyl, —(CH₂)_(n)—(C₃-C₈ monocyclic cycloalkyl), —(CH₂)_(n)(C₃-C₈monocyclic cycloalkenyl), —(CH₂)_(n)—(C₈-C₁₂ bicyclic cycloalkyl), R² is—H or -halo; or pharmaceutically acceptable salt thereof in an amounteffective to reduce the animal's rate of metabolism, such that saidanimal's rate of metabolism or rate of oxygen consumption is reduced. 4.A method for treating tachycardia, the method comprising administeringto an animal in need thereof an effective amount of a compound offormula (If):

wherein A is —CH₂ONO₂; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —C₃-C₈ monocyclic cycloalkyl; and R² is —H or -halo; or apharmaceutically acceptable salt thereof, such that said tachycardia istreated.
 5. The method of claim 4, wherein said tachycardia is atrialfibrillation or a supraventricular tachycardia.
 6. The method of claim5, wherein the treating includes lowering the animal's ventricular rateto a rate of from about 60 beats per minute to about 100 beats perminute.
 7. The method of claim 5, wherein the treating includes loweringthe animal's ventricular rate to a rate of not less than about 40 beatsper minute.
 8. The method of claim 5, wherein the compound has theformula:

or a pharmaceutically acceptable salt thereof.
 9. The method of claim 8,wherein the tachycardia is atrial fibrillation or a supraventriculartachycardia.
 10. The method of claim 8, wherein the treating includeslowering the animal's ventricular rate to a rate of from about 60 beatsper minute to about 100 beats per minute.
 11. The method of claim 8,wherein the treating includes lowering the animal's ventricular rate toa rate of not less than about 40 beats per minute.
 12. A method forconverting a cardiac arrhythmia to a normal sinus rhythm, the methodcomprising administering to an animal in need thereof an effectiveamount of a compound of formula (If):

wherein A is —CH₂ONO₂; B and C are —OH; D is

A and B are trans with respect to each other; B and C are cis withrespect to each other; C and D are cis or trans with respect to eachother; R¹ is —C₃-C₈ monocyclic cycloalkyl; and R² is —H or -halo; or apharmaceutically acceptable salt thereof, such that said cardiacarrhythmia is converted to a normal sinus rhythm.
 13. The method ofclaim 12, wherein said compound has the formula:

or a pharmaceutically acceptable salt thereof.
 14. The method of claim1, wherein said cardiovascular disease is atherosclerosis, congestiveheart failure, circulatory shock, cardiomyopathy, cardiac transplant,cardioplegia, or a cardiac arrhythmia.
 15. The method of claim 1,wherein said ischemic condition is stable angina, unstable angina,myocardial ischemia, hepatic ischemia, mesenteric artery ischemia,intestinal ischemia, myocardial infarction, critical limb ischemia,chronic critical limb ischemia, erebral ischemia, acute cardiacischemia, or an ischemic disease of the central nervous system.
 16. Themethod of claim 1, wherein said reperfusion injury is a intestinalreperfusion injury, myocardial reperfusion injury; or reperfusion injuryresulting from cardiopulmonary bypass surgery, thoracoabrominal aneurysmrepair surgery, carotid endaretectomy surgery, or hemorrhagic shock. 17.The method of claim 1, wherein said diabetes is Type I diabetes, Type IIdiabetes, gestational diabetes, insulinopathy, diabetes due topancreatic disease, diabetes associated with another endocrine disease,Type A insulin resistance syndrome, Type B insulin resistance syndrome,lipatrophic diabetes, or diabetes induced by β-cell toxins.
 18. Themethod of claim 1, wherein said wasting disease is chronic wastingdisease, cancer wasting syndrome, or AIDS wasting syndrome.